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）：黑腹果蝇转录因子 dFOXO 与秀丽隐杆线虫 daf-16 和人 FOXO3a 同源。 DAF-16 通过胰岛素/IGF 信号传导进行调节，有助于控制衰老和衰老。已知 DAF-16 通过细胞非自主机制影响衰老，但我们尚不清楚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。黑腹果蝇提供了一个有用的补充模型来理解 DAF-16/FOXO 功能。果蝇的胰岛素样受体 (InR) 和胰岛素受体底物 (chico) 普遍存在组成性突变，可延缓人口和功能衰老。最近，黑腹果蝇的 dFOXO 已被克隆，并被证明可以控制生长、抗应激和饥饿表型。在新的初步数据中，我们进一步表明 dFOXO 有条件的组织特异性过度表达可延长男性和女性的寿命。值得注意的是，当 dFOXO 在成人头部脂肪体中表达时，衰老会减慢，但在腹部脂肪体或其他组织中表达时，衰老不会减慢。根据这些观察结果，我们旨在了解 dFOXO 如何通过组织特异性功能调节衰老。我们将 (1) 描述 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) 描述 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 以及胰岛素受体底物的相互作用如何影响寿命同源 chico 和 (4) 阐明与延缓衰老相关的 dFOXO 候选转录和生理靶标。