Functions and Interactions dFOXO in Drosopila Aging

dFOXO 在果蝇衰老中的功能和相互作用

• 批准号: 6818216
• 负责人: MARC TATAR
• 金额: $ 30.97万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818216
• 关键词: Drosophilidae; aging; amidohydrolases; arthropod genetics; biological signal transduction; dietary restriction; enzyme activity; fat body; gene expression; gene interaction; genetic models; genetic transcription; head; hormone regulation /control mechanism; in situ hybridization; insulin; insulin receptor; insulinlike growth factor; longevity; microarray technology; nutrition related tag; protein structure function; reproduction; transcription factor; translation factor

DESCRIPTION (provided by applicant): The D. melanogaster transcription factor dFOXO is homologous to C. elegans daf-16 and to human FOXO3a. Regulated through insulin/IGF signaling, DAF-16 helps control dauer and aging. DAF-16 is known to affect aging through cell nonautonomous mechanisms, but we do not yet know which tissues are required to initiate this regulation or how these coordinate organism-wide senescence. D. melanogaster provides a useful complementary model to understand DAF-16/FOXO function. Flies with ubiquitous, constitutive mutations at the insulin-like receptor (InR) and insulin receptor substrate (chico) retard demographic and functional aging, Recently, dFOXO of D. melanogaster has been cloned and shown to control growth, stress resistance and starvation phenotypes. In new preliminary data we further show that conditional, tissue specific over-expression of dFOXO increases longevity in both males and females. Notably, senescence is slowed when dFOXO is expressed in adult fat body of the head, but not when expressed in abdominal fat body or in other tissues. Working from these observations we aim to understand how dFOXO regulates aging through tissue specific function. We shall (1) characterize endogenous functions of dFOXO in the head fat body and describe how this tissue differs from the fat body of the abdomen, (2) characterize how longevity induced by dFOXO-expression is influenced by diet restriction and by reproduction, (3) characterize through genetic analysis how longevity is affected by the interaction of dFOXO with the histone deactylase SIR2, with the translation factor binding protein 4e-BP, and with the insulin receptor substrate homolog chico and (4) elucidate candidate transcriptional and physiological targets of dFOXO associated with slow aging.

描述（由申请人提供）：D。melanogaster转录因子DFOXO与秀丽隐杆线虫DAF-16和人类FOXO3A同源。 DAF-16通过胰岛素/IGF信号传导调节，有助于控制Dauer和衰老。已知DAF-16通过细胞非自治机制影响衰老，但我们尚不知道需要哪些组织来启动这种调节或这些范围范围的衰老。 D. Melanogaster提供了一个有用的补充模型，以了解DAF-16/FOXO功能。最近在胰岛素样受体（INR）和胰岛素受体底物（Chico）延迟人口统计学和功能衰老的无处不在，本构突变的苍蝇（最近）已被克隆并控制以控制生长，应激耐受性和饥饿表型。在新的初步数据中，我们进一步表明，dfoxo的条件，组织特异性的过表达会增加男性和女性的寿命。值得注意的是，当Dfoxo在头部的成年脂肪体中表达时，衰老会减慢，而在腹部脂肪体或其他组织中表达时不会减慢。从这些观察结果中工作，我们旨在了解DFOXO如何通过组织特定功能调节衰老。我们应（1）表征dfoxo在头部脂肪体中的内源性功能，并描述该组织与腹部的脂肪体的不同，（2）表征了DFOXO表达诱导的寿命如何受饮食限制和再现的影响，并通过遗传分析与DFFOX的互动来表征（3）。结合蛋白4E-BP，以及胰岛素受体底物Chico和（4）与缓慢衰老相关的DFOXO的候选候选转录和生理靶标。