Role of G Protein Signaling in Control of Aging

描述（由申请人提供）：我们的长期目标是了解异三聚体G蛋白和G蛋白偶联受体的信号机制和生理功能。G蛋白控制着多种生理功能。然而，G蛋白信号在控制动物衰老中的潜在作用尚未被探索。最近，我们为控制果蝇寿命的G蛋白偶联受体methuselah纯化了一种内源性肽配体，命名为寿条（中国神话中的长寿），并且编码寿条的基因突变可以延长果蝇的寿命，其程度与methuselah突变相同。这为研究G蛋白信号在寿命中心控制中的参与提供了一个非同寻常的切入点。在本次资助申请中，有两个广泛的具体目的：1 .研究果蝇的寿道-麻土撒拉系统。1)我们将进行寿道和麻土撒拉相互作用的药理学表征。2)研究寿桃配体的生物发生机制。3)研究果蝇的组织分布。4)分析寿涛突变体果蝇的抗逆性。5)我们将研究G蛋白在果蝇细胞中的偶联作用。2。小鼠寿道系统的研究。我们的长期目标是探索G蛋白信号在哺乳动物衰老控制中的作用。寿道-玛土撒拉系统提供了一个很好的起点。因此，我们将：1)构建寿涛基因敲除小鼠进行寿命研究（寿涛基因序列在小鼠中保守）；2)小鼠寿道受体的鉴定。这项研究直接关系到人类的健康。更好地了解衰老的分子机制肯定会对我们的社会有益。

DESCRIPTION (provided by applicant): Our long-term objective is to understand the signaling mechanisms and physiological functions of heterotrimeric G proteins and G protein-coupled receptors. G proteins control diverse physiological functions. However, the potential role of G protein signaling in the control of animal aging has not been explored. Recently we have purified an endogenous peptide ligand, designated as shoutao (longevity in Chinese mythology), for the G protein-coupled receptor methuselah which controls lifespan in Drosophila, and that mutations in the gene encoding shoutao extended the lifespan of the flies to the same degree as methuselah mutations. This has provided an extraordinary entry point to investigate the participation of G protein signaling in the central control of lifespan. In this grant application, there are two broad specific aims: I. Study of the shoutao-methuselah system in Drosophila. 1) We will carry out the pharmacological characterization of shoutao and methuselah interaction. 2) We will study the biogenesis of the ligand shoutao. 3) We will examine the tissue distribution of methuselah in Drosophila. 4) We will analyze the stress resistance of shoutao mutant flies. 5) We will investigate the G protein coupling by methuselah in Drosophila cells. II. Study of the shoutao system in mouse. Our long-term goal is to explore the role of G protein signaling in the control of aging in mammals. The shoutao-methuselah system provides an excellent starting point. Therefore, we will: 1) generate knockout mice for shoutao for lifespan studies (the shoutao sequence is conserved in mouse); 2) identify the receptor for shoutao in mouse. This research is directly related to human health. A better understanding of the molecular mechanism of aging will certainly benefit our society.