Functions and Interactions dFOXO in Drosopila Aging

描述（由申请人提供）：D。黑腹果蝇转录因子dFOXO与C. elegans daf-16和人FOXO 3a。通过胰岛素/IGF信号调节，β-16有助于控制衰老和衰老。已知β-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，或者这些组织如何协调整个生物体的衰老。D. melanogaster提供了一个有用的补充模型，以了解β-16/FOXO功能。在胰岛素样受体（InR）和胰岛素受体底物（chico）上存在普遍的组成性突变的果蝇延缓人口和功能衰老。黑腹果蝇已被克隆，并显示出控制生长、抗胁迫和饥饿表型。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在头部的成人脂肪体中表达时，衰老减慢，但当在腹部脂肪体或其他组织中表达时，衰老不减慢。从这些观察结果中，我们的目标是了解dFOXO如何通过组织特异性功能调节衰老。我们将（1）表征dFOXO在头部脂肪体中的内源性功能，并描述该组织如何不同于腹部脂肪体，（2）表征由dFOXO表达诱导的寿命如何受到饮食限制和生殖的影响，（3）通过遗传分析表征寿命如何受到dFOXO与组蛋白脱乙酰酶SIR 2的相互作用的影响，与翻译因子结合蛋白4 e-BP和与胰岛素受体底物同系物chico，以及（4）阐明与缓慢衰老相关的dFOXO的候选转录和生理靶点。

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.