Role of G Protein Signaling in Control of Aging

G 蛋白信号传导在控制衰老中的作用

• 批准号: 6997802
• 负责人: Xin-Yun Huang
• 金额: $ 41.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997802
• 关键词: Drosophilidae; G protein; aging; cell age; cell surface receptors; gene mutation; genetically modified animals; laboratory mouse; ligands; longevity; receptor binding; receptor coupling; stress

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.

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 蛋白信号传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，命名为“寿涛”（中国神话中的长寿），用于控制果蝇寿命的G蛋白偶联受体玛苏塞拉，并且编码“寿涛”的基因的突变使果蝇的寿命延长至相同水平。程度为methuselah突变。这为研究 G 蛋白信号传导在寿命中央控制中的参与提供了一个非凡的切入点。在本次拨款申请中，有两个广泛的具体目标： I. 研究果蝇的 Shotao-methuselah 系统。 1）我们将开展寿桃和玛撒拉相互作用的药理学表征。 2）我们将研究配体shoutao的生物发生。 3) 我们将检查 methuselah 在果蝇中的组织分布。 4)我们将分析Shouao突变体果蝇的抗逆性。 5) 我们将研究果蝇细胞中 methuselah 的 G 蛋白偶联。二.小鼠受涛系统的研究。我们的长期目标是探索 G 蛋白信号传导在控制哺乳动物衰老中的作用。 Shotao-methuselah 系统提供了一个极好的起点。因此，我们将： 1) 生成喊涛基因敲除小鼠，用于寿命研究（喊涛序列在小鼠体内是保守的）； 2) 鉴定小鼠体内“寿涛”的受体。这项研究与人类健康直接相关。更好地了解衰老的分子机制必将使我们的社会受益。