# Genetic pathway and cellular mechanism underlying organismic responses to hypoxia and hypothermia

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $375,625

## Abstract

Project Summary/Abstract
Proper temperature and oxygen levels enable essential life activities. Low temperature (hypothermia) and
reduced level of oxygen (hypoxia) pervasively influence fundamental biochemical processes, cellular
metabolism, organismic physiology and behaviors. Hypoxia and oxidative stresses are also key features in
ischemic disorders, including stroke and heart attack, treatment of which can greatly benefit from the emerging
procedure of “therapeutic hypothermia.” Our laboratory is interested in fundamental genetic analysis and
mechanistic studies of hypoxia, hypothermia, innate ischemic tolerance in resilient organisms, and
cytoprotection against tissue injuries caused by metabolic stresses. We use 1) genetically tractable C. elegans
mutants isolated from large-scale screens with abnormal cell physiological and organismic behavioral
phenotypes in hypoxia/hypothermia responses and 2) Mangrove Killifish, the only known self-fertilizing
vertebrate with genetics similar to that of C. elegans and known extreme physiological phenotypes related to
hypoxia and hypothermia, as discovery tools. In addition, we culture mammalian neural stem cells ex vivo
isolated from hibernating ground squirrels to unravel cellular intrinsic mechanisms of hypoxia/hypothermia
tolerance. With multidisciplinary approaches and technologies, we have been running a productive research
program and already discovered novel mechanisms of action of genes, protein variants and pathways in
conferring cytoprotection and organismic responses to hypoxia and hypothermia. In this R35 application, we
propose to continue these tractable and innovative lines of inquiries to expand our basic understanding of how
cells and organisms cope with hypoxia and hypothermia, to characterize novel genes and pathways already
identified from our forward genetic and RNAi screens, and to identify key genetic determinants of innate
hypoxia/ischemic tolerance in resilient organisms. The PI and laboratory's extensive prior experience and
expertise in diverse but complementary model systems are well suited for executing and successfully
completing the project in the Cardiovascular Research Institute at the University of California, San Francisco
(UCSF). As the MIRA R35 is intended to “enable consolidation of NIGMS support for multiple projects that may
be disparate” as is our case, we will balance efforts and resources dedicated to each of the model systems,
which are similarly tractable towards addressing the same core questions in our research program.

## Key facts

- **NIH application ID:** 10322162
- **Project number:** 5R35GM139618-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Dengke Ma
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,625
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322162

## Citation

> US National Institutes of Health, RePORTER application 10322162, Genetic pathway and cellular mechanism underlying organismic responses to hypoxia and hypothermia (5R35GM139618-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322162. Licensed CC0.

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