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Project Title:  Extended Culture of Kidney MPS and Organoids to Model Acute and Chronic Exposure to Drugs and Environmental Toxins Reduce
Images: icon  Fiscal Year: FY 2024 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Cell & Molecular Biology  
Start Date: 11/15/2022  
End Date: 11/14/2026  
Task Last Updated: 12/14/2023 
Download Task Book report in PDF pdf
Principal Investigator/Affiliation:   Yeung, Catherine  Ph.D. / University of Washington 
Address:  4333 BROOKLYN AVE NE 
 
Seattle , WA 98195 
Email: cathyy@uw.edu 
Phone: 206-799-2374  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Washington 
Joint Agency: NIH, BARDA, FDA 
Comments:  
Co-Investigator(s)
Affiliation: 
Bammler, Theodor  Ph.D. University of Washington 
Freedman, Benjamin  Ph.D. University of Washington 
Himmelfarb, Jonathan  Ph.D. University of Washington 
Kelly, Edward  Ph.D. University of Washington 
Thummel, Kenneth  Ph.D. University of Washington 
Zelnick, Leila  Ph.D. University of Washington 
Project Information: Grant/Contract No. 80ARC023CA001  
Responsible Center: NASA HQ 
Grant Monitor: Koniges, Ursula  
Center Contact: 202-256-8786 
ursula.m.koniges@nasa.gov 
Unique ID: 15769 
Solicitation / Funding Source: 2021 Space Biology NNH21ZDA015N. Extended Longevity of 3D Tissues and Microphysiological Systems for Modeling of Acute and Chronic Exposures to Stressors 
Grant/Contract No.: 80ARC023CA001  
Project Type: GROUND 
Flight Program:  
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:  
Space Biology Element: (1) Cell & Molecular Biology
Space Biology Cross-Element Discipline: None
Space Biology Special Category: (1) Cell Culture
Flight Assignment/Project Notes: Per the Research Announcement for this solicitation: this effort is a collaboration between NASA; the National Institutes of Health (NIH); the Biomedical Advanced Research and Development Authority (BARDA); and the Food and Drug Administration (FDA).

Task Description: Kidney disease is a public health problem affecting 850 million people worldwide, 37 million people in the US adult population, and is the 9th leading cause of death. Loss of kidney function is often associated with chronic hypertension, diabetes, or exposure to pathogens, drugs, or environmental chemicals, and in many cases, takes many months or years to manifest clinically. Finding efficacious therapeutics and preventing disease progression require fundamentally new strategies, assays, and models of the kidney to improve patient outcomes. Until recently, the lack of human in vitro models that recapitulate critical aspects of kidney physiology, mimic the unique complexities of specific nephron segments, model disease heterogeneity, or assess reparative mechanisms in response to injury has hindered progress.

Our team has approached the scientific challenges of studying kidney disease pathophysiology, novel therapeutic agents, and drug/ environmental toxicity by establishing two innovative human models: the proximal tubule kidney chip microphysiological system (PTEC MPS) and the iPSC (induced pluripotent stem cell)-derived kidney organoid. We have developed validation assays for short-duration (2-10 day) exposures in both ground-based laboratories and aboard the International Space Station. The goal of this project is to demonstrate models with extended (6 month) longevity to better understand the role of chronic stressor exposure on kidney disease initiation and progression. Based on previous studies, we hypothesize that human kidney systems will remain viable and functionally stable for at least 6 months and will respond physiologically to extended exposure to stressors.

Phase I – Description and Tasks. Establish extended longevity and functionality (6 months) of kidney microphysiological systems and organoids. The contractor shall: • Determine longevity of the proximal tubule kidney chip (PTEC) MPS at 2.5, 5, and 6 months by employing cell viability (live/dead staining), metabolic function (conversion of 25(OH)VitaminD3 to 1a25(OH)2 VitaminD3), toxic response (resulting in KIM-1 [kidney injury molecule-1] expression), stable expression of immunomodulators (e.g., IL[interleukin]-6, IL-23A, TNF [tumor necrosis factor], IL-32), and global RNA transcript profile. • Determine longevity and stable function of kidney organoids at 2.5, 5, and 6 months by conducting observation of distinct tubules with specific multiple nephron and stromal lineages in segmented structures (immunocytochemical staining), and stable global single cell RNA transcript profile.

Phase II – Description and Tasks. Test structural and functional outcomes after sustained exposure to drugs, environmental toxins, and pathogens and post-exposure cellular recovery. The contractor shall: • Determine functional outcomes of PTEC MPS after exposure to agents known to cause nephrotoxicity after 5 months exposure (PMB [polymyxin B] or other nephrotoxin) followed by 1 month recovery by evaluating structural derangement (de-polarization of transporter proteins), production of injury biomarkers (KIM-1, HO-1 [heme oxygenase-1], cystatin), and altered regulation of immunomodulators (e.g., IL-6, IL-23A, TNF, IL-32). • Evaluate kidney organoid responses to pathogenic stimuli and known nephrotoxins using fluorescent reporters for real-time detection of infection and injury in response to acute (3 days) and extended (5 months) exposure followed by 1 month of recovery.

Research Impact/Earth Benefits: Developing a kidney microphysiological system and kidney organoids with extended longevity will allow us to model the effects of stressors like drugs, environmental toxins, pathogens, and microgravity on kidney cell structure and function, and to determine if, and how, kidney cells can recover from stress. A better understanding of kidney injury and recovery from chronic stressor exposure can accelerate the development of better and safer medications and treatments to prevent and cure kidney diseases.

Task Progress & Bibliography Information FY2024 
Task Progress: We have demonstrated MPS viability and maintenance of tubular conformation for 6 months as shown by brightfield and fluorescence (green-fluorescent calcein-AM and red-fluorescent ethidium homodimer-1) microscopy. Of six lumens seeded, three survived to six months and two continue to show >90% viability at almost 10 months. We have demonstrated stable function of PTEC MPS tubules by observing stable secretion of KIM-1 (Kidney Injury Molecule-1) and IL-6 over 5-6 months of culture. RNA for RNAseq analysis has been extracted from all tubules from 0-6 months and are pending analysis and informatics.

We have also been able to maintain viable kidney organoids for at least six months. Kidney organoid structure and organization was consistent throughout the experiment. To analyze function, we demonstrated proximal tubule function in the kidney organoids via dextran absorption over the course of the experiment, supporting the idea that these cells were functional after 180 days. We have collected and analyzed RNA from organoids on day 25 and day 180 for single cell RNA sequencing.

Dr. Edward Kelly, a Co-Investigator on this grant, also contributed to a National Academies of Sciences Decadal Survey publication entitled, "Thriving in space: Ensuring the future of biological and physical sciences research: A decadal survey for 2023-2032." [Ed. Note: See Bibliography.]

Bibliography: Description: (Last Updated: 12/14/2023) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Jones-Isaac KA, Lidberg KA, Yang J, Bain J, Ruiz M, Koenig G, Koenig P, Countryman S, Himmelfarb J, Yeung CK, Kelly EJ. "Development of a kidney microphysiological system hardware platform for microgravity studies." ISSRDC 2023 (International Space Station Research and Development Conference), Seattle, WA, July 31-Aug 3, 2023. Poster.

Abstracts. ISSRDC 2023 (International Space Station Research and Development Conference), Seattle, WA, July 31-Aug 3, 2023. , Jul-2023

Abstracts for Journals and Proceedings Lidberg KA, Jones-Isaac KA, Bain JD, Yang J, Calamia J, Thummel KE, Yeung CK, Countryman S, Koenig P, Himmelfarb J, Kelly EJ. "Impact of microgravity on a three-dimensional microphysiologic culture of the human kidney proximal tubule epithelium: Cell response to serum and vitamin D." American Society for Gravitational and Space Research Annual Meeting, Washington DC, November 14-18, 2023. Poster.

Abstracts. American Society for Gravitational and Space Research Annual Meeting, Washington DC, November 14-18, 2023. , Nov-2023

Articles in Other Journals or Periodicals National Academies of Sciences, Engineering, and Medicine. "Thriving in space: Ensuring the future of biological and physical sciences research: A decadal survey for 2023-2032." Washington, DC: The National Academies Press, 2023. Prepublication. https://doi.org/10.17226/26750 , Sep-2023
Project Title:  Extended Culture of Kidney MPS and Organoids to Model Acute and Chronic Exposure to Drugs and Environmental Toxins Reduce
Images: icon  Fiscal Year: FY 2023 
Division: Space Biology 
Research Discipline/Element:
Space Biology: Cell & Molecular Biology  
Start Date: 11/15/2022  
End Date: 11/14/2026  
Task Last Updated: 12/14/2023 
Download Task Book report in PDF pdf
Principal Investigator/Affiliation:   Yeung, Catherine  Ph.D. / University of Washington 
Address:  4333 BROOKLYN AVE NE 
 
Seattle , WA 98195 
Email: cathyy@uw.edu 
Phone: 206-799-2374  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Washington 
Joint Agency: NIH, BARDA, FDA 
Comments:  
Co-Investigator(s)
Affiliation: 
Bammler, Theodor  Ph.D. University of Washington 
Freedman, Benjamin  Ph.D. University of Washington 
Himmelfarb, Jonathan  Ph.D. University of Washington 
Kelly, Edward  Ph.D. University of Washington 
Thummel, Kenneth  Ph.D. University of Washington 
Zelnick, Leila  Ph.D. University of Washington 
Project Information: Grant/Contract No. 80ARC023CA001 
Responsible Center: NASA HQ 
Grant Monitor:  
Center Contact:   
Unique ID: 15769 
Solicitation / Funding Source: 2021 Space Biology NNH21ZDA015N. Extended Longevity of 3D Tissues and Microphysiological Systems for Modeling of Acute and Chronic Exposures to Stressors 
Grant/Contract No.: 80ARC023CA001 
Project Type: GROUND 
Flight Program:  
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:  
Space Biology Element: (1) Cell & Molecular Biology
Space Biology Cross-Element Discipline: None
Space Biology Special Category: (1) Cell Culture
Flight Assignment/Project Notes: Per the Research Announcement for this solicitation: this effort is a collaboration between NASA; the National Institutes of Health (NIH); the Biomedical Advanced Research and Development Authority (BARDA); and the Food and Drug Administration (FDA).

Task Description: Kidney disease is a public health problem affecting 850 million people worldwide, 37 million people in the US adult population, and is the 9th leading cause of death. Loss of kidney function is often associated with chronic hypertension, diabetes, or exposure to pathogens, drugs, or environmental chemicals, and in many cases, takes many months or years to manifest clinically. Finding efficacious therapeutics and preventing disease progression require fundamentally new strategies, assays, and models of the kidney to improve patient outcomes. Until recently, the lack of human in vitro models that recapitulate critical aspects of kidney physiology, mimic the unique complexities of specific nephron segments, model disease heterogeneity, or assess reparative mechanisms in response to injury has hindered progress.

Our team has approached the scientific challenges of studying kidney disease pathophysiology, novel therapeutic agents, and drug/ environmental toxicity by establishing two innovative human models: the proximal tubule kidney chip microphysiological system (PTEC MPS) and the iPSC (induced pluripotent stem cell)-derived kidney organoid. We have developed validation assays for short-duration (2-10 day) exposures in both ground-based laboratories and aboard the International Space Station. The goal of this project is to demonstrate models with extended (6 month) longevity to better understand the role of chronic stressor exposure on kidney disease initiation and progression. Based on previous studies, we hypothesize that human kidney systems will remain viable and functionally stable for at least 6 months and will respond physiologically to extended exposure to stressors.

Phase I – Description and Tasks. Establish extended longevity and functionality (6 months) of kidney microphysiological systems and organoids. The contractor shall: • Determine longevity of the proximal tubule kidney chip (PTEC) MPS at 2.5, 5, and 6 months by employing cell viability (live/dead staining), metabolic function (conversion of 25(OH)VitaminD3 to 1a25(OH)2 VitaminD3), toxic response (resulting in KIM-1 [kidney injury molecule-1] expression), stable expression of immunomodulators (e.g., IL[interleukin]-6, IL-23A, TNF [tumor necrosis factor], IL-32), and global RNA transcript profile. • Determine longevity and stable function of kidney organoids at 2.5, 5, and 6 months by conducting observation of distinct tubules with specific multiple nephron and stromal lineages in segmented structures (immunocytochemical staining), and stable global single cell RNA transcript profile.

Phase II – Description and Tasks. Test structural and functional outcomes after sustained exposure to drugs, environmental toxins, and pathogens and post-exposure cellular recovery. The contractor shall: • Determine functional outcomes of PTEC MPS after exposure to agents known to cause nephrotoxicity after 5 months exposure (PMB [polymyxin B] or other nephrotoxin) followed by 1 month recovery by evaluating structural derangement (de-polarization of transporter proteins), production of injury biomarkers (KIM-1, HO-1 [heme oxygenase-1], cystatin), and altered regulation of immunomodulators (e.g., IL-6, IL-23A, TNF, IL-32). • Evaluate kidney organoid responses to pathogenic stimuli and known nephrotoxins using fluorescent reporters for real-time detection of infection and injury in response to acute (3 days) and extended (5 months) exposure followed by 1 month of recovery.

Research Impact/Earth Benefits: Developing a kidney microphysiological system and kidney organoids with extended longevity will allow us to model the effects of stressors like drugs, environmental toxins, pathogens, and microgravity on kidney cell structure and function, and to determine if, and how, kidney cells can recover from stress. A better understanding of kidney injury and recovery from chronic stressor exposure can accelerate the development of better and safer medications and treatments to prevent and cure kidney diseases.

Task Progress & Bibliography Information FY2023 
Task Progress: New Project for FY2023

Bibliography: Description: (Last Updated: 12/14/2023) 

Show Cumulative Bibliography
 
 None in FY 2023