NSF Org:	CBET Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient:	UNIVERSITY OF CALIFORNIA, SAN DIEGO
Initial Amendment Date:	July 20, 2021
Latest Amendment Date:	July 20, 2021
Award Number:	2126309
Award Instrument:	Standard Grant
Program Manager:	Rizia Bardhan rbardhan@nsf.gov  (703)292-2390 CBET  Division of Chemical, Bioengineering, Environmental, and Transport Systems ENG  Directorate for Engineering
Start Date:	October 1, 2021
End Date:	September 30, 2024 (Estimated)
Total Intended Award Amount:	$400,000.00
Total Awarded Amount to Date:	$400,000.00
Funds Obligated to Date:	FY 2021 = $400,000.00
History of Investigator:	Alysson Muotri (Principal Investigator) muotri@ucsd.edu Erik Viirre (Co-Principal Investigator)
Recipient Sponsored Research Office:	University of California-San Diego 9500 GILMAN DR LA JOLLA CA  US  92093-0021 (858)534-4896
Sponsor Congressional District:	50
Primary Place of Performance:	University of California-San Diego 9500 Gilman Drive, MC 0695 La Jolla CA  US  92093-0695
Primary Place of Performance Congressional District:	50
Unique Entity Identifier (UEI):	UYTTZT6G9DT1
Parent UEI:
NSF Program(s):	Engineering of Biomed Systems
Primary Program Source:	01002122DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s):	8091
Program Element Code(s):	534500
Award Agency Code:	4900
Fund Agency Code:	4900
Assistance Listing Number(s):	47.041

ABSTRACT

This project will study brain aging and inflammation in microgravity. Long-term space exposure creates a series of physiological alterations including cognitive decline. Studying astronauts' brains before and after their mission can tell what goes wrong but provides little insight on the mechanisms responsible for the observed alterations. This, this project will grow stem cell-derived human brain tissues at the International Space Station to accelerate our understanding of the mechanisms involved in brain aging. These studies will have profound implications for improved neurological pre-clinical models for applications on Earth. Educational benefits from this investigation include incorporating the results into the training of graduate students and high school students. The work will also be disseminated to the broader community through a video channel and podcast episodes.

Microgravity has been shown to evoke alterations in cell growth, differentiation, cell communication, aging, and epigenetic/gene expression alterations in various cell types, including brain cells. Preliminary data, from a previous spaceflight, showed exposure to microgravity induced a series of molecular changes that mimic aging in human cells. Such alterations might accelerate or enhance cellular (telomerase dynamics) and molecular processes (activation of endogenous retroelements) that are important for neurological disorders. Here, this study will mechanistically investigate this aging phenotype on human brain organoids infused with microglia. First, the brain organoids will be optimized for spaceflight compatibility. Second, the impact of re-activation of endogenous retroelements will be characterized. And third, brain organoids will be generated with inducible TERT and modulate their activity at different developmental stages to determine how telomerase activity affects the development of brain organoids. The proposed work will advance understanding of 3D brain organoids enabling improved models of neurological disorders that represent significant health burdens.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Several neurological symptoms, including cognitive dysfunction, have been reported in astronauts in space missions. However, the mechanisms by which these changes occur and if this phenomenon could be leveraged to study neurological conditions on Earth have yet to be explored. Here, we used human brain organoids (stem cell-derived brain tissues made in the lab) to examine the impact of the space environment on human brain cells aboard the International Space Station (ISS). First, we have developed and optimized a novel hardware to autonomously cultivate human brain organoids at the ISS with minimal astronaut manipulation. Such hardware sucessfully maintein the brain organoids for 30 days at the ISS. Moreover, using transcriptomics and proteomics, we found that space-exposed brain organoids activated age-related pathways usually silenced on Earth under non-pathological conditions. Also, the period in space changed the different cell populations in the brain organoids. Intinguing, we also detected an activated viral pathways that triggered an neurotoxic inflammaroty response, decreasing synaptogenesis and increasing inflammation, which was rescued using anti-viral inhibitors. Using low-Earth orbit as a tool to understand its impact on the human brain can also help better understand neurodevelopmental mechanisms on Earth, and develop disease modeling strategies to test novel therapeutic opportunties for neurological conditions with no cure.

Last Modified: 11/04/2024
Modified by: Alysson R Muotri

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