Task Progress:
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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 GCRs. 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 a broad assay for altered protein expression and changes in protein function, which may lead to genetic and proteomic interventions targeting 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 hiPSCs and are well characterized.
The specific aims are: (1) Characterizing responses of 3D models of human vasculature, neurovascular, and cardiac tissues to exposure to space radiation; (2) An integrative systems-medicine approach to identifying therapeutic targets for minimizing space-radiation-induced damage; and (3) Developing and testing countermeasures using optogenetics and protein antagonist therapies to protect human tissue from radiation damage.
Preliminary findings following the first year of the project indicate that simulated GCR potentially poses a significant risk to vascular, heart, and neurovascular health. Following GCR exposure experiments, we also note the need to adjust our 3D tissue models to continue with the proposed experiments. Computational network models of drug-gene interactions that integrate across numerous data sources were created. Finessing our proteomic cell extraction protocols and workflow to fit the 3D tissue models is in progress. Countermeasure development continues with the establishment of the Opto-fibroblast growth factor receptor (Opto-FGFR) hiPSC line and engineering an antagonist to target HMGB1.
Our findings thus far do not alter our original hypothesis or the objective and aims as originally proposed. Ongoing modifications to our technologies and protocols would support the proposed experimental plan and will continue into next year. We will continue to characterize responses of the human complex model for space radiation, integrate advanced computational techniques for multi-scale modeling proteome, and begin testing countermeasures.
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Additional progress notes from PI (Ed., 10/12/22)
• While still within the preliminary stages of the research project, we have putatively identified key consequences of simulated GCR exposure on our 3D human tissues. • Improvements to our model systems are enabling us to perform in depth analyses of radiation impact. • Key modifications were made to identify protocols for cell extraction from the 3D human model systems for downstream molecular analysis. • Refinements of proteomics workflows for operating on small amounts of material were made. • Computational network models of drug-gene interactions that integrate across numerous data sources were created. • Using optogenetics we began to develop a potential countermeasure to GCR in the human iPSC line. • Ongoing countermeasure development work is designing a novel anti-inflammatory protein that promises to have utility in preventing radiation damage. • Our successful presentation of the HMGB1 box A domain on the yeast surface display platform empowers new directions in engineering immunomodulatory proteins as targeted drugs. • Monte Carlo simulations of the GCR blocker enabling us to determine the experimental exposures to more closely reflect the field that would be incurred by these cells at the depth in tissues during spaceflight.
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Articles in Peer-reviewed Journals
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Chancellor JC, Nowadly C, Williams JA, Aunon-Chancellor SM, Chesal M, Looper J, Newhauser W. "Everything you wanted to know about space radiation but were afraid to ask." J Environ Sci Health C Toxicol Carcinog. 2021 Apr 27;39(2):113-28. https://doi.org/10.1080/26896583.2021.1897273 ; PubMed PMID: 33902392 , Apr-2021
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Articles in Peer-reviewed Journals
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Nguyen J, Lin Y, Gerecht S. "The next generation of endothelial differentiation: Tissue-specific ECs." Cell Stem Cell. 2021 Jul 1;28(7):1188-204. https://doi.org/10.1016/j.stem.2021.05.002 ; PubMed PMID: 34081899 , Jul-2021
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Articles in Peer-reviewed Journals
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Macklin BL, Lin YY, Emmerich K, Wisniewski E, Polster BM, Konstantopoulos K, Mumm JS, Gerecht S. "Intrinsic epigenetic control of angiogenesis in induced pluripotent stem cell-derived endothelium regulates vascular regeneration." npj Regen Med. 2022 May 12;7:28. https://pubmed.ncbi.nlm.nih.gov/35551465 ; PubMed PMID: 35551465; PubMed Central PMCID: PMC9098630 , May-2022
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Articles in Peer-reviewed Journals
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Schnellmann R, Ntekoumes D, Choudhury MI, Sun S, Wei Z, Gerecht S. "Stiffening matrix induces age-mediated microvascular phenotype through increased cell contractility and destabilization of adherens junctions." Adv Sci (Weinh). 2022 Aug;e2201483. https://pubmed.ncbi.nlm.nih.gov/35657074 ; PubMed PMID: 35657074; PubMed Central PMCID: PMC9353494 , Aug-2022
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Articles in Peer-reviewed Journals
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Yarbrough D, Gerecht S. "Engineering smooth muscle to understand extracellular matrix remodeling and vascular disease." Bioengineering. 2022 Sep 7;9(9):449. https://doi.org/10.3390/bioengineering9090449 ; PubMed PMID: 36134994; PubMed Central PMCID: PMC9495899 , Sep-2022
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Articles in Peer-reviewed Journals
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Sharma A, Clemens RA, Garcia O, Taylor DL, Wagner NL, Shepard KA, Gupta A, Malany S, Grodzinsky AJ, Kearns-Jonker M, Mair DB, Kim DH, Roberts MS, Loring JF, Hu J, Warren LE, Eenmaa S, Bozada J, Paljug E, Roth M, Taylor DP, Rodrigue G, Cantini P, Smith AW, Giulianotti MA, Wagner WR. "Biomanufacturing in low Earth orbit for regenerative medicine." Stem Cell Reports. 2022 Jan 11;17(1):1-13. https://doi.org/10.1016/j.stemcr.2021.12.001 ; PubMed PMID: 34971562; PubMed Central PMCID: PMC8758939 , Jan-2022
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Articles in Peer-reviewed Journals
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Bokhari RS, Beheshti A, Blutt SE, Bowles DE, Brenner D, Britton R, Bronk L, Cao X, Chatterjee A, Clay DE, Courtney C, Fox DT, Gaber MW, Gerecht S, Grabham P, Grosshans D, Guan F, Jezuit EA, Kirsch DG, Liu Z, Maletic-Savatic M, Miller KM, Montague RA, Nagpal P, Osenberg S, Parkitny L, Pierce NA, Porada C, Rosenberg SM, Sargunas P, Sharma S, Spangler J, Tavakol DN, Thomas D, Vunjak-Novakovic G, Wang C, Whitcomb L, Young DW, Donoviel D. "Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel." Life Sci Space Res (Amst). 2022 Nov;35:105-12. https://doi.org/10.1016/j.lssr.2022.08.003 . Epub 2022 Aug 7. PMID: 36336356 , Nov-2022
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Awards
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Gerecht, S. "Fellow of the American Association for the advancement of Science (AAAS), January 2021." Jan-2021
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Awards
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Gerecht, S. "Member of the National Academy of Inventors (NAI), December 2020." Dec-2020
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