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Dissecting a Novel Genetic Pathway for Fatty Acid Desaturation and Temperature Adaptation

剖析脂肪酸去饱和和温度适应的新遗传途径

基本信息

批准号：
9979942
负责人：
Dengke Ma
金额：
$ 28.01万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979942
关键词：
Affect Anti-Inflammatory Agents Archaea Area Bacteria Biochemical Process Biological Biological Assay Blood Vessels CRISPR/Cas technology Caenorhabditis elegans California Cardiovascular system Cell membrane Cells Cellular biology Coenzyme A Complement Data Disease Doctor of Philosophy Eukaryota Fatty Acids Fatty acid glycerol esters Genes Genetic Genetic Epistasis Genetic Screening Goals Hereditary Disease Homeostasis Homologous Gene Human Human Cell Line Hyperthermia Hypoxia Inflammatory Knowledge Learning Life Lipids Malignant Neoplasms Mammalian Cell Mammals Mediating Membrane Fluidity Metabolic Metabolic Diseases Modernization Molecular Mutation Neurologic Normal Range Orthologous Gene Oxygen PPAR alpha Pathway Analysis Pathway interactions Peroxisome Proliferator-Activated Receptors Phenotype Postdoctoral Fellow Process Property Protein Family Receptor Signaling Reporter Research Institute Research Personnel Role San Francisco Saturated Fatty Acids Signal Transduction Site Stearoyl-CoA Desaturase Syndrome System Temperature Testing Training Universities Unsaturated Fatty Acids Validation acyl-CoA dehydrogenase adiponectin base behavioral response desaturase experience experimental study fatty acid metabolism fatty acid oxidation fluidity gene discovery genetic approach genome sequencing human model innovation insight insulin sensitizing drugs investigator training member mutant new therapeutic target novel oxidation positional cloning public health relevance receptor response therapeutic target transcription factor unpublished works whole genome

项目摘要

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.

描述（由申请人提供）：细胞调节脂质去饱和和膜流动性，以响应温度变化维持体内平衡。这一基本过程发生在几乎所有形式的生命中，但其在真核生物中的潜在机制在很大程度上是未知的。从一个C。在探索基因如何控制对氧的敏感性的线虫筛选中，我们发现了一种新的途径，包括基因egl-25和acdh-11（酰基辅酶A脱氢酶，ACDH），其通过硬脂酰辅酶A去饱和酶（SCD）FAT-7促进温度适应（未发表）。egl-25编码C.哺乳动物脂联素受体的elegans同源物，其在哺乳动物中具有有效的胰岛素增敏、抗氧化和抗炎特性。人类ACDH缺乏导致最常见的脂肪酸氧化遗传性疾病，其综合征会因体温过高而加重，类似于C。线虫acdh-11突变体对热的敏感性。SCD通过催化脂肪酸去饱和的限制步骤来控制膜流动性，并且它们的失调导致代谢紊乱和癌症。该项目的目标是利用我们的初步发现，创新的生物测定和强大的遗传方法在C。利用分子生物学方法鉴定与egl-25/acdh-11相互作用的新基因突变，以表征egl-25/acdh-11在控制脂肪代谢中的功能作用，酸代谢、去饱和和信号传导（Aim II），并阐明在C. elegans和人类细胞（Aim III）。这位新研究者之前的培训经验和C.线虫遗传筛选和哺乳动物细胞信号传导非常适合于在加州大学心血管研究所进行该项目，旧金山弗朗西斯科（UCSF）。该提议具有高影响力的潜力，因为它应该1）揭示通过新的脂肪酸信号传导模式驱动温度适应的新的保守途径，并表明由ACDH缺乏引起的热敏感性表型的机制基础，阐明egl-25/acdh的作用机制和调节因子。11途径，这将为治疗包括代谢和血管炎性疾病在内的人类疾病提供新的治疗靶点。