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Project Title:  Using Human Stem-Cell Derived Vascular, Neural, and Cardiac 3D Tissues to Determine Countermeasures for Radiation Reduce
Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
TRISH--TRISH 
Start Date: 10/01/2020  
End Date: 09/30/2023  
Task Last Updated: 12/02/2020 
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Principal Investigator/Affiliation:   Gerecht, Sharon  Ph.D. / Johns Hopkins University 
Address:  Department of Chemical and Biomolecular Engineering 
3400 North Charles St 
Baltimore , MD 21218 
Email: gerecht@jhu.edu 
Phone: 410-516-2846  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Johns Hopkins University 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Boehler, Kenneth  Ph.D. Johns Hopkins University 
Chancellor, Jeffrey  Ph.D. Louisiana State University 
Hienz, Robert  Ph.D. Johns Hopkins University 
Kim, Deok-Ho  Ph.D. Johns Hopkins University 
Lee, Gabsang   Ph.D. Johns Hopkins University 
Shelhamer, Mark  Sc.D. Johns Hopkins Medical School 
Xu, Jinchong  Ph.D. Johns Hopkins University 
Tung, Leslie  Ph.D. Johns Hopkins University 
Spangler, Jamie  Ph.D. Johns Hopkins University 
Mallick, Parag  Ph.D. Stanford University 
Project Information: Grant/Contract No. NNX16AO69A-RAD0102 
Responsible Center: TRISH 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2020 TRISH Space Radiation Solicitation TSRAD-2020. Translational Research Institute for Space Health (TRISH) Human-Based Models to Study Effects of Space Radiation and Countermeasures 
Grant/Contract No.: NNX16AO69A-RAD0102 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
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Human Research Program Elements: None
Human Research Program Risks: None
Human Research Program Gaps: None
Task Description: In this study a skilled team with diverse expertise will examine 3D human tissue models for their response to radiation, with an eye to the development of countermeasures. Cardiovascular and neuronal degeneration are established risks of exposure to deep-space radiation (galactic cosmic rays, GCR). Inflammation and oxidative damage are dominant mechanisms, which are being addressed with appropriate pharmaceuticals or supplements. There are, however, various forms of protein modification including oxidation, reduction, and changes in expression. These have been demonstrated at relatively high dosages with terrestrial radiation sources, providing an impetus for further investigation into damage mechanisms that impact protein structure and function. Thus, we propose here a broad assay for altered protein expression and changes in protein function, which may lead to genetic and proteomic interventions that target the most-affected sites. This is complemented with an investigation of the signaling pathways that might propagate these effects.

We analyze responses of three human tissue models to low-dose protracted GCR simulations, and identify and develop countermeasures using optogenetics and molecular antagonists. Human tissue models include vascular, cerebrovascular, and cardiac. These are 3D constructs generated from human pluripotent stem cells (hPSCs) and are well characterized.

Radiation exposures are in alignment with NASA guidelines. In a slight departure, we make use of a newly developed method to modify the standard GCR beam at NASA Space Radiation Laboratory (NSRL) in order to provide a GCR spectrum that better emulates one inside a spacecraft. This alleviates some of the concerns with the existing radiation sources, and provides a more direct transfer of our results to the actual spaceflight situation.

The project is organized into three specific aims. First, we determine the effect of radiation exposure on cell viability and cell cycle, tissue integrity and functionality, and the activation of oxidative stress and high mobility group box 1 (HMGB1) pathways. This will validate the usefulness of our biological models, and radiation exposures, for the subsequent investigation of countermeasures. Second, we use an integrative systems approach to identify therapeutic (countermeasure) targets to mitigate radiation damage. This is accomplished with large- scale quantitative proteomics, multi-data fusion and network analysis, and conformational inhibition tests. Ultimately, in aim three, we develop and test countermeasures based on optogenetics and protein antagonists, to activate or inhibit pathways impacted by radiation.

The results of this project will help to determine if complex human models can serve as an effective test bed for the effects of space radiation on intact humans, and will identify and assess possible countermeasures to these effects.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2021 
Task Progress: New project for FY2021.

Bibliography Type: Description: (Last Updated: )  Show Cumulative Bibliography Listing
 
 None in FY 2021