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源三聚体G蛋白和G蛋白偶联受体的信号传导机制和生理功能。G蛋白控制多种生理功能。然而，G蛋白信号转导在控制动物衰老中的潜在作用尚未被探索。最近，我们纯化了一种内源性肽配体，称为寿桃（中国神话中的长寿），用于控制果蝇寿命的G蛋白偶联受体玛士撒拉，并且编码寿桃的基因突变延长了果蝇的寿命与玛士撒拉突变的程度相同。这为研究G蛋白信号在寿命中枢控制中的参与提供了一个非凡的切入点。在这项拨款申请中，有两个广泛的具体目标：一。果蝇寿桃-玛士撒拉系统的研究1)我们将开展寿桃和玛士撒拉相互作用的药理学表征。2)我们将研究配体寿桃的生物起源。3)我们将研究玛士撒拉在果蝇中的组织分布。4)我们将分析寿桃突变果蝇的抗逆能力。5)我们将在果蝇细胞中研究玛士撒拉对G蛋白的偶联作用。二.小鼠寿桃系统的研究。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。寿桃-玛士撒拉系统提供了一个很好的起点。因此，我们将：1）产生用于寿命研究的寿桃基因敲除小鼠（寿桃序列在小鼠中是保守的）; 2）鉴定小鼠中寿桃的受体。这项研究直接关系到人类健康。更好地了解衰老的分子机制肯定会使我们的社会受益。

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.