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: 6937123
• 负责人: MARC TATAR
• 金额: $ 34万
• 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/6937123
• 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。通过胰岛素/IGF信号调控，DAF-16有助于控制衰老。已知DAF-16通过细胞非自主机制影响衰老，但我们还不知道哪些组织需要启动这种调节，也不知道这些组织如何协调整个生物体的衰老。D. melanogaster为理解DAF-16/FOXO功能提供了一个有用的补充模型。具有普遍存在的胰岛素样受体（InR）和胰岛素受体底物（chico）组成突变的果蝇延缓了人口统计学和功能性衰老。最近，黑腹果蝇的dFOXO基因被克隆并显示出控制生长、抗逆性和饥饿表型。在新的初步数据中，我们进一步表明有条件的、组织特异性的dFOXO过表达增加了男性和女性的寿命。值得注意的是，当dFOXO在成人头部脂肪体中表达时，衰老速度减慢，而在腹部脂肪体或其他组织中表达时，衰老速度减慢。根据这些观察结果，我们的目标是了解dFOXO如何通过组织特定功能调节衰老。我们将(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脂肪体的不同之处；(2)表征dFOXO表达诱导的寿命如何受到饮食限制和繁殖的影响；(3)通过遗传分析表征dFOXO与组蛋白脱乙酰酶SIR2、翻译因子结合蛋白4e-BP的相互作用如何影响寿命。并与胰岛素受体底物同源chico和(4)阐明与慢衰老相关的dFOXO的候选转录和生理目标。