Functions and Interactions dFOXO in Drosopila Aging

描述(申请人提供)：黑腹葡萄球菌转录因子dFOXO与线虫daf-16同源，与人FOXO3a同源。通过胰岛素/胰岛素样生长因子信号调节，DAF-16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，但我们还不知道哪些组织需要启动这一调节，或者这些组织如何协调整个生物体的衰老。D.Blackogaster为了解DAF-16/FOXO功能提供了一个有用的补充模型。果蝇的胰岛素样受体(INR)和胰岛素受体底物(CHICO)上普遍存在的结构性突变延缓了果蝇的人口和功能衰老，最近，黑腹果蝇的dFOXO已被克隆并被证明控制生长、抗逆性和饥饿表型。在新的初步数据中，我们进一步表明，条件的、组织特异性的dFOXO过度表达延长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，衰老是缓慢的，但当dFOXO在腹部脂肪体或其他组织中表达时，则不会。通过这些观察，我们的目标是了解dFOXO如何通过组织特异性功能来调节衰老。我们将(1)鉴定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)鉴定由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dFOXO与组蛋白去乙酰基酶Sir2、翻译因子结合蛋白4E-BP以及与胰岛素受体底物同源基因ChICO的相互作用如何影响寿命；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.