2016 — 2020 |
Ma, Dengke |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissecting a Novel Genetic Pathway For Fatty Acid Desaturation and Temperature Adaptation @ University of California, San Francisco
? DESCRIPTION (provided by applicant): Cells adjust lipid desaturation and membrane fluidity to maintain homeostasis in response to temperature shifts. This fundamental process occurs in nearly all forms of life, but its underlying mechanism in eukaryotes is largely unknown. From a C. elegans screen exploring how genes control sensitivity to oxygen, we discovered a novel pathway comprising the genes egl-25 and acdh-11 (acyl-CoA dehydrogenase, ACDH) that facilitates temperature adaptation via the stearoyl-CoA desaturase (SCD) FAT-7 (unpublished). egl-25 encodes a C. elegans homolog of the mammalian receptors for adiponectin, which has potent insulin-sensitizing, anti- oxidative and anti-inflammatory properties in mammals. Human ACDH deficiency causes the most common inherited disorders of fatty acid oxidation, with syndromes that are exacerbated by hyperthermia, analogous to the vulnerability of C. elegans acdh-11 mutants to heat. SCDs control membrane fluidity by catalyzing the limiting step of fatty acid desaturation, and their dysregulation causes metabolic disorders and cancer. The goals of this project are to leverage our preliminary findings, innovative bioassays and powerful genetic approaches in C. elegans to molecularly identify mutations defining new genes interacting with egl-25/acdh-11 (Aim I), to characterize the functional roles of egl-25/acdh-11 in controlling fatty acid metabolism, desaturation and signaling (Aim II), and to elucidate the similarity and mechanisms of action of key egl-25/acdh-11 pathway components that are conserved in C. elegans and human cells (Aim III). This new investigator's prior training experience and areas of expertise in C. elegans genetic screens and mammalian cell signaling are well suited for carrying out this project in the Cardiovascular Research Institute at the University of California, San Francisco (UCSF). This proposal has the potential for high impact because it should 1) reveal a novel conserved pathway that drives temperature adaptation via a new mode of fatty acid signaling and suggests a mechanistic basis of the thermo-sensitivity phenotype caused by ACDH deficiency, and 2) elucidate mechanisms and regulators of the egl-25/acdh-11 pathway that should provide novel therapeutic targets for treating human conditions including metabolic and vascular inflammatory disorders.
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0.915 |
2021 |
Ma, Dengke |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Genetic Pathway and Cellular Mechanism Underlying Organismic Responses to Hypoxia and Hypothermia @ University of California, San Francisco
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.
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0.915 |