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

 描述(申请人提供)：细胞调节脂肪去饱和度和膜流动性，以维持体内平衡，以响应温度变化。这一基本过程几乎发生在所有形式的生命中，但其在真核生物中的潜在机制在很大程度上是未知的。从研究基因如何控制对氧气的敏感性的线虫中，我们发现了一个新的途径，包括基因EGL-25和acdh-11(酰辅酶A脱氢酶，ACDH)，通过硬脂酰辅酶A脱氢酶(SCD)FAT-7促进温度适应(未发表)。EGL-25编码哺乳动物脂联素受体的线虫同源物，脂联素在哺乳动物中具有强大的胰岛素增敏、抗氧化和抗炎特性。人类ACDH缺乏会导致最常见的脂肪酸氧化遗传性疾病，高热会加剧这些综合征，类似于线虫acdh-11突变体对高温的脆弱性。SCDS通过催化脂肪酸去饱和的限制步骤来控制膜的流动性，它们的失调会导致代谢紊乱和癌症。这个项目的目标是利用我们在线虫中的初步发现、创新的生物检测方法和强大的遗传方法来从分子上鉴定定义与egl-25/acdh-11(Aim I)相互作用的新基因的突变，以表征egl-25/acdh-11在控制脂肪中的功能作用。 目的：阐明线虫和人类细胞中保守的EGL-25/acdh-11途径关键成分的相似性和作用机制(Aim III)。这位新的研究人员在线虫基因筛选和哺乳动物细胞信号方面的先前培训经验和专业领域非常适合在加州大学心血管研究所开展这一项目， 旧金山(加州大学旧金山分校)。这一建议具有很大的潜在影响，因为它应该1)揭示一种新的保守途径，通过一种新的脂肪酸信号模式驱动温度适应，并提出ACDH缺乏引起的温度敏感性表型的机制基础；2)阐明EGL-25/acdh-11途径的机制和调节，这将为治疗包括代谢和血管炎症在内的人类疾病提供新的治疗靶点。

 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(acyl-CoA dehydrogenase, ACDH) that facilitates temperature adaptation via the stearoyl-CoA desaturase (SCD) FAT-7 (unpublished).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.