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Project Title:  Sex- and Apo E-specific Late CNS and Cardiovascular Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2018  
End Date: 05/31/2022  
Task Last Updated: 06/05/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Lemere, Cynthia  Ph.D. / Brigham and Women's Hospital/Harvard Medical School 
Address:  75 Francis Street 
 
Boston , MA 02115-6110 
Email: clemere@bwh.harvard.edu 
Phone: 617-954-9697  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Taylor, Doris  Ph.D. Texas Heart Institute 
Hochman Mendez, Camila  Ph.D. Texas Heart Institute 
Key Personnel Changes / Previous PI: June 2021: As reported last year, Dr. Doris Taylor, a Co-Investigator on this grant, recently left Texas Heart Institute (THI). She has appointed Dr. Camila Hochman Mendez of THI as the interim Co-Investigator until Dr. Taylor finds a new research home. The switch has been approved by THI and Brigham & Women's Hospital (BWH) Research Administration.
Project Information: Grant/Contract No. 80NSSC18K0810 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC18K0810 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Task Description: Our overall objective is to determine the short- and long-term risks of radiation from the space environment on cognition, motor abilities, fatigue resistance, anxiety, and changes in the brain and cardiovascular system. In our first grant period, we determined that low-dose 56Fe (iron) radiation had long-term, sex-specific consequences on cognition, locomotion, neuroinflammation, and Alzheimer's disease (AD) pathogenesis, with males being more vulnerable than females. Analysis of proton-irradiated mice showed some overlapping yet some opposing effects compared to iron. We have developed a collaboration with Drs. Doris Taylor and Camila Hochman Mendez (Texas Heart Institute), Co-Investigators on this proposal, by sharing the heart, one kidney, and bone marrow from each of the mice irradiated in three of our studies. During the current grant period, we will extend our research by comparing our existing data from our current studies on the late central nervous system (CNS) and cardiovascular (CV) effects of a single dose of iron radiation or a single dose of protons with a single dose of 5-ion, mixed beam simulated galactic cosmic radiation (GCRsim) in male and female AD-like transgenic and wildtype mice, and gamma irradiated wildtype mice (Aim 1). In addition, we will examine the sex- and Apo E-specific late CNS and CV dose-specific effects of iron radiation in a novel AD-like mouse model modified by targeted replacement of murine Apo E with human Apo E3 or E4 to determine if human ApoE4, a strong risk factor for AD and CV disease, exacerbates the effects of radiation (Aim 2). This work will be conducted in collaboration with investigators at Wash U, Duke U, and the RIKEN Brain Institute. We will perform longitudinal Magnetic Resonance Imaging (MRI) on the brain and heart in a subset of mice in Aims 1 and 2 to determine radiation-induced changes within individual animals. Heart and kidneys will be examined by our THI collaborators. In addition, mice will undergo extensive behavioral testing as well as pathological and biochemical analysis of brain and heart. Lastly, we will conduct a study to test 2 novel human 3D neural models of Alzheimer's disease, developed by our collaborators at Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT) (Aim 3), for acute and late CNS effects of space radiation on neuronal health, amyloid plaques, tau pathology, and epigenetics, and to investigate the potential of these models for screening mitigating treatments in the future. In collaboration with Drs. Taylor and Hochman Mendez, we will also irradiate differentiated induced pluripotent stem cell (iPSCs)-derived cardiomyocytes and endothelial cells from human males and females to determine whether GCRsim or gamma irradiation alters their gene expression, morphology or function. In summary, we propose to take our current studies to the next logical step in an effort to better understand the potential risks of galactic cosmic radiation (GCR) to the brain and cardiovascular system in order to prepare astronauts for long-term deep space mission, including missions to the moon and Mars.

Research Impact/Earth Benefits: The overall goal of our research is to better assess the central nervous system and cardiovascular risks to astronauts during and after deep space travel. To properly understand these risks in the diverse human population, we must account for how sex and genetic differences change the way radiation damage manifests. Our work characterizing these radiation-disease models will also create platforms for testing strategies for mitigating radiation damage to improve the safety and long-term health of the astronauts.

Task Progress & Bibliography Information FY2021 
Task Progress: During the first 4 years of our NASA-funded program, we determined that mice exposed to relatively small doses of single components of space radiation (iron nuclei or protons) resulted in changes in behavior, cognition, and brain health. These changes were dependent on the sex and underlying genetic disease susceptibility of the mice as well as on the specific dose received. Interestingly, we found that young adult female mice were more resistant than male mice to the effects of space radiation on cognition and Alzheimer’s disease-like damage. Here, we are extending these studies to examine the effects of a mixed-ion simulation of space-like radiation, known as “simulated Galactic Cosmic Radiation” (GCRsim) at doses predicted for astronauts traveling on long-term missions into deep space. GCRsim includes a mix of protons, silicon, helium, oxygen and iron ions.

Our current mouse studies (Aims 1 and 2) examine how sex differences and multiple genetic risk factors for Alzheimer’s disease modify GCRsim radiation-induced changes in behavior, cognition, disease progression, brain and heart structure, and inflammation in the brain, heart, and kidney. Aim 1 builds upon our previous single-ion (iron and proton) studies but tests low-dose space-like mixed 5-ion GCRsim radiation exposure in the same Alzheimer’s amyloid mouse model and wildtype mice. Aim 2 investigates the effects of a strong vascular Alzheimer’s risk factor Apolipoprotein E4 in another, more physiologically relevant Alzheimer’s “knock-in” mouse model and wildtype mice in response to low-dose GCRsim radiation. Equal numbers of female and male mice are included in each study. Due to the large number of mice required to achieve a statistically significant result, we have divided each of the mouse studies into two staggered cohorts to facilitate breeding, experimentation and analyses. We perform pre-irradiation and post-irradiation MRI scans of the brain and heart in a subset of mice. The rest of the mice undergo a 10-test behavioral battery that we developed during our first 4 years of funding to evaluate locomotion, strength, fatigue resistance (endurance), motor coordination, sensorimotor effects, psychological state, learning, and memory in mice. In addition, we utilize several novel human brain cell cultures (Aim 3), derived from immortalized progenitor neural cells and induced pluripotent stem cells (iPSCs) differentiated to neurons and glia, to investigate how space-like radiation affects human brain health in the context of specific disease-associated genetic factors. Our collaborators, Dr. Taylor and Dr. Camila Hochman Mendez (Texas Heart Institute, THI), are exploring the effects of space-like radiation on the heart and kidneys of our mice from Aims 1 and 2, as well as assessing GCRsim effects on heart cell function and maturation from irradiated iPSC-derived cardiomyocytes and endothelial cells in Aim 3. All experiments include additional mice or cell cultures exposed to gamma radiation (similar to x-rays) for comparison with those exposed to the space-like GCRSim radiation. This aids us in interpreting our findings to understand radiation risk to humans. These studies involve strong collaborations with researchers at the Texas Heart Institute, Massachusetts General Hospital, Massachusetts Institute of Technology, Brookhaven National Laboratory (BNL), Duke University, Washington University School of Medicine, NYU School of Medicine, the RIKEN Brain Institute in Japan, the Harvard School of Medicine Mouse Behavior Core, the Brigham & Women’s Hospital Department of Radiology, and the NASA Ames Research Center.

For Aim 1, we have now completed the irradiation, MRI scanning, behavioral analyses, sacrifice, and tissue collection of all mice. We bred and aged two identical cohorts of 114 mice per cohort, including female and male Alzheimer’s-like transgenic (Tg) mice and wildtype (WT) mice, staggered ~5-6 months apart. Mice underwent pre-irradiation (IRR) MRI scans of brain and heart at 3.5 months of age, were transported to Brookhaven National Laboratory (BNL) for low-dose GCRsim IRR (0.5 or 0.75 Gy; WT and Tg) or gamma IRR (0.75 or 2 Gy; WT only), and were returned to BWH where they later underwent behavioral testing and post-IRR MRI scans prior to sacrifice and tissue harvest at 13 months of age. Of the 228 mice at the start of the study, a total of 184 mice survived until the end of the study. Roughly half of the female Tg died prematurely, regardless of radiation exposure, similar to what we and others have previously observed. Male Tg and all WT mice had few, if any, premature deaths. A total of 124 of the mice underwent extensive behavioral testing at 12-13 months of age, while 60 mice underwent follow-up MRI scanning of the brain and heart. In terms of behavior, GCRsim and gamma IRR worsened spatial memory in male WT mice but not females or Tg mice. This is similar to our previous findings with single ion IRR (56-iron or protons) which also worsened memory in male mice but not females and suggests that low doses of space-like radiation induced sex-specific, long-lasting effects on brain function. Male WT mice had reduced sensorimotor gating compared to female WT mice without radiation, while both GCRsim and gamma IRR reduced sensorimotor gating in female WT mice. In the rotarod test for motor coordination, female Tg mice were able to hold onto the rotating rod longer than all other mice but GCRsim IRR caused them to fall off the rod sooner. Male Tg mice exposed to low-dose GCRsim stayed on the rod longer, suggesting they had improved motor coordination. Gamma IRR had no effect on motor coordination in male or female WT mice. Male Tg mice exposed to GCRsim were better able to resist fatigue (i.e., had better endurance) in the wire hanging test than non-irradiated mice. Importantly, no radiation-specific effects were observed for fear learning and memory, startle response, or anxiety- or depressive-like behaviors in any of the mouse groups.

Comparison of pre- to post-IRR brain MRI scans indicated reduced cortical volume in female and male WT mice exposed to GCRsim and gamma IRR and increased ventricular volume in female WT and male Tg mice exposed to GCRsim, both of which are suggestive of brain atrophy. In contrast, GCRsim IRR increased hippocampal volume in male WT and male Tg mice while gamma IRR increased it in female and male WT mice. We will stain brain sections to confirm hippocampal volume changes and look for signs of neurogenesis or peripheral cell infiltration. Amyloid-beta, a protein that aggregates and forms plaques in Alzheimer’s disease brain, was higher in female Tg than male Tg mouse brain, as seen previously with this mouse model, but GCRsim IRR had no effect. Previously, we found that Abeta levels were increased in male Tg mice exposed to iron IRR, a small component of the GCRsim exposure. Further brain analyses are underway. Regarding the cardiac studies, the MRI scans revealed no radiation-specific effects on heart structure or function. Our collaborators at THI measured gene expression changes in the heart and kidney. Interestingly, there were strong, long-lasting, radiation-induced gene expression changes in the heart and kidney following low-dose GCRsim exposure, but less so with gamma IRR. In particular, GCRsim IRR reduced the expression of genes in the heart needed to break down fats to use as energy and to transport glucose in WT and Tg mice. It also reduced genes involved in pathological tissue remodeling and fibrosis and inflammatory pathways. In kidney, GCRsim IRR reduced the expression of genes involved in DNA damage repair and pathological tissue remodeling and fibrosis, and increased expression of a glycoprotein found on immune cells to facilitate their transmigration across endothelial cells. Mouse hearts and kidneys are being examined histologically.

For Aim 2, we were somewhat delayed by the COVID-19 pandemic. We have now bred and aged 272 novel Alzheimer’s-like amyloid knock-in (KI) mice that express either human APOE E3 or E4, the latter of which is the strongest risk factor for Alzheimer’s disease after aging. Equal numbers of female and male mice were subjected to low-dose GCRsim IRR at BNL in May 2021. A second cohort will be subjected to GCRsim and gamma IRR at BNL in June 2021. Pre-IRR MRI scans were performed on a subset of 32 mice. Behavioral testing, MRI follow-up scans, and analysis of blood, brain, heart and kidney will begin in Spring 2022.

For Aim 3, we have completed several studies at BNL using human 3D neural cultures derived from immortalized progenitor cells, called ReNcells, some of which express Alzheimer’s disease-associated mutations. This “brain-in-a-dish” paradigm was developed by our collaborators, Drs. Rudy Tanzi and Doo Yong Kim at MGH. We demonstrated the feasibility of transporting these cultures between Boston and Long Island and have collected data on how radiation affects disease progression. In general, we see a consistent increase in amyloid-beta protein levels following gamma IRR but not GCRsim IRR. Amyloid production was not elevated, suggesting that gamma IRR caused an impairment in breakdown or clearance of amyloid protein. Thus far, we have seen very little change in tau or phosphorylated tau protein (which is one of the hallmarks of Alzheimer’s disease). Radiation increased the release of inflammatory molecules called cytokines. Adding brain immune cells called microglia to the cultures after GCRsim IRR resulted in migration of the microglia towards the neurons in wildtype, non-Alzheimer’s cell cultures and increased secretion of immune molecules after gamma IRR in Alzheimer’s-like cell cultures. Cytokines were elevated after adding microglia, regardless of whether the neural cultures had been exposed to radiation or not. In addition, we recently irradiated human stem cell (iPSC)-derived brain cells with different forms of Apolipoprotein E including APOE4, APOE3, APOE2, and cells lacking APOE. Gamma radiation exposure increased the overall levels of insoluble amyloid-beta but reduced the insoluble (aggregated) amyloid-beta 42/40 ratio in the fluid bathing the E4, E2, and KO cell cultures. In contrast, gamma radiation increased the soluble amyloid-beta 42/49 ratio in all 4 cell lines while GCRsim increased it in the E3 and E2 lines. A subset of these cells was shipped to the NASA Ames Research Center for single cell RNA sequencing by our collaborators. Lastly, our THI collaborators shipped human stem cell (iPSC)-derived cardiomyocytes and endothelial cells to BNL where we exposed them to GCRsim and gamma radiation in May 2021. A duplicate experiment will be run in June 2021. The cells were shipped back to THI in Houston to look for radiation-induced changes in gene expression, cell morphology and for cardiomyocytes, electrical changes.

The overall goal of our research is to better assess the central nervous system and cardiovascular risks to astronauts during and after deep space travel. To properly understand these risks in the diverse human population, we must account for how sex and genetic differences change the way radiation damage manifests. Our work characterizing these radiation-disease models will also create platforms for testing strategies for mitigating radiation damage to improve the safety and long-term health of the astronauts.

Bibliography Type: Description: (Last Updated: 04/29/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Hinshaw RG, Park J, Kim DY, Tanzi RE, Lemere CA. "Space-like and gamma radiation-induced pathology changes in an in vitro human cell model of Alzheimer's Disease." 66th Annual Meeting of Radiation Research Society, Virtual Meeting, October 18-21, 2020.

Conference proceedings. 66th Annual Meeting of Radiation Research Society, Virtual Meeting, October 18-21, 2020. , Oct-2020

Abstracts for Journals and Proceedings Schroeder MK, Khan KA, Caldarone BJ, Lemere CA. "Long-term Behavioral Effects of Mixed-ion Irradiation on Wildtype C57BL/6J and Alzheimer’s-like APPswe/PS1dE9 Mice." 66th Annual Meeting of Radiation Research Society, Virtual Meeting, October 18-21, 2020.

Conference proceedings 66th Annual Meeting of Radiation Research Society, Virtual Meeting, October 18-21, 2020. , Oct-2020

Abstracts for Journals and Proceedings Hinshaw RG, Park J, Kim DY, Tanzi RE, Lemere CA. "Radiation-Induced Pathology Changes in an in vitro Human Cell Model of Alzheimer's Disease." Discover Brigham Research Day 2020, Virtual Event, November 2020.

Conference proceedings -- online abstracts. Discover Brigham Research Day 2020, Virtual Event, November 2020. , Nov-2020

Abstracts for Journals and Proceedings Schroeder MK, Khan KA, Caldarone BJ, Lemere CA. "Long-term Behavioral Effects of Mixed-ion Irradiation on Wildtype C57BL/6J and Alzheimer’s-like APPswe/PS1dE9 Mice." Discover Brigham Research Day 2020, Virtual Event, November 2020.

Meeting proceedings -- abstracts online. Discover Brigham Research Day 2020, Virtual Event, November 2020. , Nov-2020

Abstracts for Journals and Proceedings Khan KA, Schroeder MK, Price BR, Caldarone B, Lemere CA. "Long-term CNS effects of GCRsim and gamma irradiation in male and female wildtype and Alzheimer’s-like mice." Discover Brigham Research Day 2020, Virtual Event, November 2020.

Meeting proceedings - abstracts online. Discover Brigham Research Day 2020, Virtual Event, November 2020. , Nov-2020

Abstracts for Journals and Proceedings Schroeder MK, Khan KA, Caldarone BJ, Lemere CA. "Long-term Behavioral Effects of Mixed-ion Irradiation on Wildtype C57BL/6J and Alzheimer’s-like APPswe/PS1dE9 Mice." 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

Abstract in IWS proceedings - online. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Hinshaw RG, Park J, Kim DY, Tanzi RE, Lemere CA. "Radiation Dose-dependent Alterations of Amyloid Pathology in Human Cell Models of Alzheimer’s Disease." 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

Abstract in IWS proceedings - online. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Khan KA, Price BR, Schroeder MK, Ding J, Lemere CA. "MRI Analysis of Wildtype and Alzheimer’s-like Mice Pre-and Post- Low Dose GCRSIM and Gamma Irradiation." 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

Abstract in IWS proceedings - online. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Schroeder MK, Price BR, Khan KA, Caldarone B, Lemere CA. "Long-term CNS Effects of Low-dose Simulated Galactic Cosmic Radiation and Gamma Irradiation on Wildtype and Alzheimer’s-like Mice." 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

Abstract in IWS proceedings - online. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Hinshaw RG, Park J, Kim DY, Tanzi RE, Lemere CA. "New Human Neural Cell Models of Low-Dose Space-Like Radiation Exposure." 23rd IAA Humans in Space Symposium, Virtual (Moscow, Russia), April 5-8, 2021.

Abstract in conference proceedings online. 23rd IAA Humans in Space Symposium, Virtual (Moscow, Russia), April 5-8, 2021. , Apr-2021

Abstracts for Journals and Proceedings Schroeder MK, Price BR, Khan KA, Caldarone B, Lemere CA. "Long-term CNS Effects of Low-dose Galactic Cosmic Radiation on Wildtype and Alzheimer’s-like Mice." 23rd IAA Humans in Space Symposium, Virtual (Moscow, Russia), April 5-8, 2021.

Abstract in conference proceedings - online. 23rd IAA Humans in Space Symposium, Virtual (Moscow, Russia), April 5-8, 2021. , Apr-2021

Project Title:  Sex- and Apo E-specific Late CNS and Cardiovascular Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2018  
End Date: 05/31/2022  
Task Last Updated: 05/24/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Lemere, Cynthia  Ph.D. / Brigham and Women's Hospital/Harvard Medical School 
Address:  75 Francis Street 
 
Boston , MA 02115-6110 
Email: clemere@bwh.harvard.edu 
Phone: 617-954-9697  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Taylor, Doris  Ph.D. Texas Heart Institute 
Hochman Mendez, Camila  Ph.D. Texas Heart Institute 
Key Personnel Changes / Previous PI: May 2020 report: Dr. Doris Taylor, a Co-Investigator on this grant, recently left Texas Heart Institute (THI). She has appointed Dr. Camila Hochman Mendez of THI as the interim Co-Investigator until Dr. Taylor finds a new research home. The switch has been approved by THI and Brigham & Women's Hospital (BWH) Research Administration.
Project Information: Grant/Contract No. 80NSSC18K0810 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC18K0810 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Task Description: Our overall objective is to determine the short- and long-term risks of radiation from the space environment on cognition, motor abilities, fatigue resistance, anxiety, and changes in the brain and cardiovascular system. In our first grant period, we determined that low-dose 56Fe (iron) radiation had long-term, sex-specific consequences on cognition, locomotion, neuroinflammation, and Alzheimer's disease (AD) pathogenesis, with males being more vulnerable than females. Analysis of proton-irradiated mice showed some overlapping yet some opposing effects compared to iron. We have developed a collaboration with Drs. Doris Taylor and Camila Hochman Mendez (Texas Heart Institute), Co-Investigators on this proposal, by sharing the heart, one kidney, and bone marrow from each of the mice irradiated in three of our studies. During the current grant period, we will extend our research by comparing our existing data from our current studies on the late central nervous system (CNS) and cardiovascular (CV) effects of a single dose of iron radiation or a single dose of protons with a single dose of 5-ion, mixed beam simulated galactic cosmic radiation (GCRsim) in male and female AD-like transgenic and wildtype mice, and gamma irradiated wildtype mice (Aim 1). In addition, we will examine the sex- and Apo E-specific late CNS and CV dose-specific effects of iron radiation in a novel AD-like mouse model modified by targeted replacement of murine Apo E with human Apo E3 or E4 to determine if human ApoE4, a strong risk factor for AD and CV disease, exacerbates the effects of radiation (Aim 2). This work will be conducted in collaboration with investigators at Wash U, Duke U, the RIKEN Brain Institute, and NYU (New York University). We will perform longitudinal Magnetic Resonance Imaging (MRI) on the brain and heart in a subset of mice in Aims 1 and 2 to determine radiation-induced changes within individual animals. In addition, mice will undergo extensive behavioral testing as well as pathological and biochemical analysis of brain and heart. Lastly, we will conduct a study to test 2 novel human 3D neural models of Alzheimer's disease, developed by our collaborators at Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT) (Aim 3), for acute and late CNS effects of space radiation on neuronal health, amyloid plaques, tau pathology, and epigenetics, and to investigate the potential of these models for screening mitigating treatments in the future. In collaboration with Drs. Taylor and Hochman Mendez, we will also irradiate undifferentiated induced pluripotent stem cells (iPSCs) from human males and females to determine whether highly charged, high energy (HZE) particle irradiation alters their ability to differentiate into cardiomyocytes, morphology, and/or maturation. In summary, we propose to take our current studies to the next logical step in an effort to better understand the potential risks of galactic cosmic radiation (GCR) to the brain and cardiovascular system in order to prepare astronauts for long-term deep space mission, including missions to the moon and Mars.

Research Impact/Earth Benefits: The overall goal of our research is to better assess the central nervous system and cardiovascular risks to astronauts during and after deep space travel. To properly understand these risks in the diverse human population, we must account for how sex and genetic differences change the way radiation damage manifests. Our work characterizing these radiation-disease models will also create platforms for testing strategies for mitigating radiation damage to improve the safety and long-term health of the astronauts.

Task Progress & Bibliography Information FY2020 
Task Progress: During the first 4 years of our NASA-funded program, we determined that mice exposed to relatively small doses of single components of space radiation (iron nuclei or protons) resulted in changes in behavior, cognition, and brain health. These changes were dependent on the sex and underlying genetic disease susceptibility of the mice as well as on the specific dose received. Interestingly, we found that young adult female mice were more resistant than male mice to the effects of space radiation on cognition and Alzheimer’s disease-like damage. Our collaborator, Dr. Doris Taylor (Texas Heart Institute), found similar dependencies of radiation-induced changes in heart and kidney tissues from these same mice. In our current successor grant, we are extending these studies to examine the effects of a mixed-ion simulation of space-like radiation, known as “simulated Galactic Cosmic Radiation” (GCRsim) at doses predicted for astronauts traveling on long-term missions into deep space.

Our current mouse studies (Aims 1 and 2) examine how sex differences and multiple genetic risk factors for Alzheimer’s disease modify GCRsim radiation-induced changes in behavior, cognition, disease progression, brain and heart structure, and inflammation in the brain, heart, and kidney. Aim 1 builds upon our previous single-ion (iron and proton) studies but uses space-like mixed 5-ion GCRsim radiation exposure in the same Alzheimer’s mouse model and wildtype mice. Aim 2 investigates the effects of a strong vascular Alzheimer’s risk factor Apolipoprotein E4 in the same Alzheimer’s mouse model and wildtype mice in response to GCRsim radiation. Equal numbers of female and male mice are included in each study. Due to the large number of mice required to achieve a statistically significant result, we have divided each of the mouse studies into two staggered cohorts to facilitate breeding, experimentation, and analyses. We use a 10-test behavioral battery that we developed during our first 4 years of funding to evaluate locomotion, strength, fatigue resistance, motor coordination, sensorimotor effects, psychological state, learning, and memory in mice. In addition, we utilize several novel human brain cell cultures (Aim 3), derived from immortalized progenitor neural cells and induced pluripotent stem cells (iPSCs) differentiated to neurons and glia, to investigate how space-like radiation affects human brain health in the context of specific disease-associated genetic factors.

Our collaborators, Dr. Taylor and Dr. Camila Hochman Mendez (THI), are exploring the effects of space-like radiation on the heart and kidneys of our mice from Aims 1 and 2, as well as assessing GCRsim effects on heart cell function and maturation from irradiated iPSCs in Aim 3. All experiments include additional mice or cell cultures exposed to gamma radiation for comparison with those exposed to the space-like GCRSsim radiation. This aids us in interpreting our findings to understand radiation risk to humans. These studies involve strong collaborations with researchers at the Texas Heart Institute, Massachusetts General Hospital, Massachusetts Institute of Technology, Brookhaven National Laboratory, Duke University, Washington University School of Medicine, NYU School of Medicine, the RIKEN Brain Institute in Japan, the Harvard School of Medicine Mouse Behavior Core, and the Brigham & Women’s Hospital Department of Radiology. To date, we have performed 2 in vivo radiation studies in mice for Aim 1. We bred and aged two identical cohorts of 114 mice, including female and male Alzheimer’s-like mice and wildtype (WT) mice, staggered ~5-6 months apart. Aim 1A mice underwent pre-irradiation (IRR) MRI scans of brain and heart at 3.5 months of age, were transported to BNL for irradiationin April 2019, and were returned to BWH where they later underwent behavioral imaging and post-IRR MRI scans prior to sacrifice and tissue harvest at 12 months of age in December 2019. A total of 22 mice died prior to the end of the study, with female Alzheimer’s mice having the highest attrition rate. The brains, hearts, and kidneys of the remaining 92 mice are currently undergoing analyses. Thus far, the preliminary data analysis of our behavioral studies from the first of two cohorts (and combining sexes) has revealed only a few effects of radiation. Locomotion was unaltered by GCRsim or gamma radiation. AD-like mice irradiated with 0.75 Gy GCRsim appeared to be less anxious whereas WT mice exposed to 2 Gy gamma radiation showed a tendency to be more anxious than non-irradiated mice. GCRsim irradiation had no effect on grip strength but 0.75 Gy gamma irradiation reduced grip strength in WT mice. Radiation, in general, had no effect on fatigue resistance but WT mice irradiated with 0.5 Gy GCRsim showed a hint of reduced fatigue resistance in one measure. WT mice that were irradiated with 0.75 Gy GCRsim had deficits in spatial memory, whereas gamma radiation had no effect. Depressive-like behaviors were not altered by radiation. As expected, brain levels of the Alzheimer’s protein Ab42 were higher in female than male 12 month-old Alzheimer’s-like mice, as previously demonstrated; however, no radiation-specific effects were observed. Cardiac MRI analysis revealed no genotype or radiation effects on heart structure or function. Heart and kidney tissues are being examined for radiation-induced changes gene expression and proteins related to fibrosis, inflammation, and cardiovascular function. Brain MRI analysis is ongoing. Pathological analyses will begin upon re-opening of the lab following the COVID-19 shutdown. Aim 1B mice, identical to Aim 1A, underwent pre-IRR MRI scans of brain and heart and irradiation at BNL in Oct 2019. These mice will undergo behavioral testing and post-IRR MRI scans at BWH in June 2020, followed by sacrifice and tissue harvest.

For Aim 2, we have obtained approval and breeding pairs of the specific type of mice needed to assess the role of the Apo E4 in a novel Alzheimer’s-like mouse model in the radiation response. Breeding is now underway. We will breed 2 staggered cohorts, similar to Aim 1 and expect to irradiate the first cohort of Aim 2 mice with GCRsim at BNL in Spring 2021. Equal numbers of female and male mice will be included.

Regarding our cell culture experiments of Aim 3, we have completed a pilot irradiation study (May 2018) and two full irradiation studies (Nov 2018 and Apr 2019) at BNL using human neural cultures derived from immortalized progenitor cells that have been induced with Alzheimer’s disease-associated mutations. We demonstrated the feasibility of transporting these cultures between Boston and Long Island with the pilot study and have collected data on how radiation affects disease progression with the full experiment. So far, we have found that a single 2 Gy dose of gamma radiation consistently increased Ab levels 1 week and 6 weeks post-IRR, whereas GCRsim had no effect in human neural cultures bearing Alzheimer’s disease-associated mutations. We also ran a pilot study at BNL in Oct 2019 in which upon return, we plated human microglia immune cells on top of irradiated and non-irradiated human neural cells. We are currently optimizing the protocol for a future study later this year. We are also preparing for the first of the iPSC model experiments to compare the effects of GCRsim and gamma radiation in human iPSC-derived brain cells with different forms of Apolipoprotein E, including Apo E4, a major risk factor of Alzheimer’s disease. We hope to run this experiment at BNL in the Fall 2020 campaign.

Bibliography Type: Description: (Last Updated: 04/29/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Hinshaw RG, Sowa MB, Park J, Kim DY, Ranzi RE, Hada M, Lemere CA. "Exposure of in vitro Brain Cells to Simulated Space Radiation." Presented at the 16th International Congress of Radiation Research (ICRR), Manchester, UK, August 25-29, 2019.

Abstracts. 6th International Congress of Radiation Research (ICRR), Manchester, UK, August 25-29, 2019. , Aug-2019

Project Title:  Sex- and Apo E-specific Late CNS and Cardiovascular Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2018  
End Date: 05/31/2022  
Task Last Updated: 04/18/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Lemere, Cynthia  Ph.D. / Brigham and Women's Hospital/Harvard Medical School 
Address:  75 Francis Street 
 
Boston , MA 02115-6110 
Email: clemere@bwh.harvard.edu 
Phone: 617-954-9697  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Taylor, Doris  Ph.D. Texas Heart Institute 
Project Information: Grant/Contract No. 80NSSC18K0810 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC18K0810 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Task Description: Our overall objective is to determine the short- and long-term risks of radiation from the space environment on cognition, motor abilities, fatigue resistance, anxiety, and changes in the brain and cardiovascular system. Over the past 3 years, we have determined that low-dose 56Fe (iron) radiation has long-term, sex-specific consequences on cognition, locomotion, neuroinflammation, and Alzheimer's disease (AD) pathogenesis, with males being more vulnerable than females. Analysis of proton-irradiated mice is underway. Over the past year, we have developed a collaboration with Dr. Doris Taylor (Texas Heart Institute), Co-Investigator on this proposal, by sharing the heart, one kidney, and bone marrow from each of the mice irradiated in three of our studies. Over the next 4 years, we will extend our research by comparing our existing data from our current studies on the late central nervous system (CNS) and cardiovascular (CV) effects of a single dose of iron radiation or a single dose of protons with a single dose of oxygen-16 or mixed beam galactic cosmic radiation (GCR) (protons, oxygen-16, and iron) in male and female AD-like transgenic and wildtype mice, and gamma irradiated wildtype mice (Aim 1). In addition, we will examine the sex- and Apo E-specific late CNS and CV dose-specific effects of iron radiation in the same AD-like mouse model modified by targeted replacement of murine Apo E with human Apo E3 or E4 to determine if human ApoE4, a strong risk factor for AD and CV disease, exacerbates the effects of radiation (Aim 2). This work will be conducted in collaboration with investigators at Wash U, Duke U, and NYU. We will perform longitudinal Magnetic Resonance Imaging (MRI) on the brain and heart in a subset of mice in Aims 1 and 2 to determine radiation-induced changes within individual animals. In addition, mice will undergo extensive behavioral testing as well as pathological and biochemical analysis of brain and heart. Lastly, we will conduct a study to test 2 novel human 3D neural organoid models of Alzheimer's disease, developed by our collaborators at Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT). (Aim 3), for acute and late CNS effects of space radiation on neuronal health, amyloid plaques, tau pathology, and epigenetics, and to investigate the potential of these models for screening mitigating treatments in the future. In collaboration with Dr. Taylor, we will also irradiate undifferentiated induced pluripotent stem cells (iPSCs) from human males and females to determine whether highly charged, high energy (HZE) particle irradiation alters their ability to differentiate into cardiomyocytes, morphology, and/or maturation. In summary, we propose to take our current studies to the next logical step in an effort to better understand the potential risks of galactic cosmic radiation (GCR) to the brain and cardiovascular system in order to prepare astronauts for long-term deep space mission, including missions to Mars.

Research Impact/Earth Benefits: The overall goal of our research is to better assess the central nervous system and cardiovascular risks to astronauts during and after deep space travel. To properly understand these risks in the diverse human population, we must account for how sex and genetic differences change the way radiation damage manifests. Our work characterizing these radiation-disease models will also create platforms for testing strategies for mitigating radiation damage to improve the safety and long-term health of the astronauts.

Task Progress & Bibliography Information FY2019 
Task Progress: Over the past 4 years, we have demonstrated that, when mice are exposed to relatively small doses of single components of space radiation (iron nuclei or protons), the resulting changes in behavior, cognition, and brain health depend on the sex and underlying genetic disease susceptibility of the mice as well as on the specific dose received. Interestingly, we found that young adult female mice are more resistant than male mice to the effects of space radiation on cognition and Alzheimer’s disease-like damage. Our collaborator, Dr. Doris Taylor (Texas Heart Institute), found similar dependencies of radiation-induced changes in heart and kidney tissues from these same mice. In our current successor grant, we are extending these studies to examine the effects of a mixed-component simulation of space radiation at doses predicted for astronauts traveling on long-term missions into deep space.

Our current mouse studies (Aims 1 and 2) will examine how sex differences and multiple genetic risk factors for cardiovascular and Alzheimer’s disease modify radiation-induced changes in behavior, cognition, disease progression, brain and heart structure, and inflammation in the brain, heart, and kidney. We will continue to use an 11-test behavioral battery that we developed during our first 4 years of funding to evaluate general health, strength, fatigue resistance, motor coordination, sensorimotor effects, psychological state, learning, and memory in mice. In addition, we will utilize several novel human brain cell cultures (Aim 3), derived from immortalized progenitor cells and induced pluripotent stem cells (iPSCs), to investigate how space-like radiation affects human brain health in the context of specific disease-associated genetic factors. Dr. Taylor’s lab will assess the effects of this radiation on heart cell function and development from irradiated iPSCs. All experiments will include additional mice or cell cultures exposed to gamma radiation for comparison with those exposed to the space-like radiation. This will aid us in interpreting our findings to understand radiation risk in humans. These studies involve strong collaborations with researchers at the Texas Heart Institute, Massachusetts General Hospital, Massachusetts Institute of Technology, Brookhaven National Laboratory (BNL), Duke University, Washington University School of Medicine, NYC School of Medicine, the Harvard School of Medicine Mouse Behavior Lab, and the Brigham & Women’s Hospital Department of Radiology.

Thus far, we have prepared mice for the first of our radiation experiments at BNL and are currently performing pre-irradiation imaging of their brains and hearts. We have also completed requirements for obtaining the specific type of mice needed to assess the role of the Apo E allele in the radiation response in the second half of our mouse experiments. Regarding the cell culture experiments, we have completed a pilot irradiation (Spring 2018 campaign) and the first full irradiation (Fall 2018 campaign) at BNL with the human neural cultures derived from immortalized progenitor cells that have been induced with Alzheimer’s disease-associated mutations. We have demonstrated the feasibility of transporting these cultures between Boston and Long Island with the pilot study and have collected initial data on how radiation affects disease progression with the full experiment. So far, we have found that non-mutant cultures show a radiation-induced reduction in a specific type of neuronal structural protein that accumulates in Alzheimer’s disease whereas the mutant cultures did not show this reduction, and we are continuing to collect more data.

We are currently growing cultures for the second full irradiation experiment in which we will let the cultures grow longer after irradiation before analyzing them and expect to detect stronger differences in Alzheimer’s disease brain changes. In addition, we will examine the response of brain immune cells to irradiated neural cells in the Fall 2019 campaign. We are also preparing for the first of the iPSC model experiments in the Spring 2020 campaign.

Bibliography Type: Description: (Last Updated: 04/29/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Hinshaw RG, Sowa MB, Park J, Kim DY, Tanzi RE, Hada M, Lemere CA. "In vitro Neural Health After Simulated Galactic Cosmic Ray Exposure: A Pilot Study." 34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018.

34th Annual Meeting of the American Society for Gravitational and Space Research, Bethesda, MD, October 31-November 3, 2018. , Nov-2018

Abstracts for Journals and Proceedings Hinshaw RG, Sowa MB, Park J, Kim DY, Tanzi RE, Hada M, Guida P, Lemere CA. "In vitro Exposure of Brain Cells with Simulated Galactic Cosmic Rays." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Abstracts for Journals and Proceedings Lemere CA, Hinshaw RG. "Sex- and Apo E-Specific Late CNS and Cardiovascular Effects of Mixed Beam Galactic Cosmic Radiation: A Preview of Upcoming Studies." 2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019.

2019 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 22-25, 2019. , Jan-2019

Project Title:  Sex- and Apo E-specific Late CNS and Cardiovascular Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 06/01/2018  
End Date: 05/31/2022  
Task Last Updated: 06/21/2018 
Download report in PDF pdf
Principal Investigator/Affiliation:   Lemere, Cynthia  Ph.D. / Brigham and Women's Hospital/Harvard Medical School 
Address:  75 Francis Street 
 
Boston , MA 02115-6110 
Email: clemere@bwh.harvard.edu 
Phone: 617-954-9697  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Brigham and Women's Hospital/Harvard Medical School 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Taylor, Doris  Ph.D. Texas Heart Institute 
Project Information: Grant/Contract No. 80NSSC18K0810 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC18K0810 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes (IRP Rev M)
Human Research Program Gaps: (1) BMed-102:Given exposures to spaceflight hazards (space radiation, isolation), how do we identify individual susceptibility, monitor molecular/biomarkers and acceptable thresholds, and validate behavioral health and CNS/neurological/neuropsychological performance measures and domains of relevance to exploration class missions? (IRP Rev L)
(2) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(3) BMed-107:What are the long-term changes and risks to astronaut health post-mission that, when using a continuity of care model, helps retrospectively identify and understand individual susceptibility (e.g., hereditary, dose, thresholds) to mitigate adverse CNS, cognitive, and behavioral health changes resulting from long-duration exploration missions, promoting the behavioral health of current and future crews? (IRP Rev L)
(4) CVD-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease (IRP Rev L)
Task Description: Our overall objective is to determine the short- and long-term risks of radiation from the space environment on cognition, motor abilities, fatigue resistance, anxiety, and changes in the brain and cardiovascular system. Over the past 3 years, we have determined that low-dose 56Fe (iron) radiation has long-term, sex-specific consequences on cognition, locomotion, neuroinflammation, and Alzheimer's disease (AD) pathogenesis, with males being more vulnerable than females. Analysis of proton-irradiated mice is underway. Over the past year, we have developed a collaboration with Dr. Doris Taylor (Texas Heart Institute), Co-Investigator on this proposal, by sharing the heart, one kidney, and bone marrow from each of the mice irradiated in three of our studies. Over the next 4 years, we will extend our research by comparing our existing data from our current studies on the late central nervous system (CNS) and cardiovascular (CV) effects of a single dose of iron radiation or a single dose of protons with a single dose of oxygen-16 or mixed beam galactic cosmic radiation (GCR) (protons, oxygen-16, and iron) in male and female AD-like transgenic and wildtype mice, and gamma irradiated wildtype mice (Aim 1). In addition, we will examine the sex- and Apo E-specific late CNS and CV dose-specific effects of iron radiation in the same AD-like mouse model modified by targeted replacement of murine Apo E with human Apo E3 or E4 to determine if human ApoE4, a strong risk factor for AD and CV disease, exacerbates the effects of radiation (Aim 2). This work will be conducted in collaboration with investigators at Wash U, Duke U, and NYU. We will perform longitudinal Magnetic Resonance Imaging (MRI) on the brain and heart in a subset of mice in Aims 1 and 2 to determine radiation-induced changes within individual animals. In addition, mice will undergo extensive behavioral testing as well as pathological and biochemical analysis of brain and heart. Lastly, we will conduct a study to test 2 novel human 3D neural organoid models of Alzheimer's disease, developed by our collaborators at Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT). (Aim 3), for acute and late CNS effects of space radiation on neuronal health, amyloid plaques, tau pathology, and epigenetics, and to investigate the potential of these models for screening mitigating treatments in the future. In collaboration with Dr. Taylor, we will also irradiate undifferentiated induced pluripotent stem cells (iPSCs) from human males and females to determine whether highly charged, high energy (HZE) particle irradiation alters their ability to differentiate into cardiomyocytes, morphology, and/or maturation. In summary, we propose to take our current studies to the next logical step in an effort to better understand the potential risks of galactic cosmic radiation (GCR) to the brain and cardiovascular system in order to prepare astronauts for long-term deep space mission, including missions to Mars.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2018 
Task Progress: New project for FY2018.

Bibliography Type: Description: (Last Updated: 04/29/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2018