Regulation of GDF11 by extracellular mechanisms

细胞外机制对 GDF11 的调节

• 批准号: 10206827
• 负责人: THOMAS B THOMPSON
• 金额: $ 58.74万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206827
• 关键词: Affect; Age; Aging; Animals; Binding; Biochemical; Biological; Biological Process; Biology of Aging; Buffers; Cleaved cell; Clinical; Clinical Trials; Complex; Coupled; Cues; Development; Engineering; Erythrocytes; Extracellular Protein; Family; Family member; Follistatin; GDF11 gene; GDF8 gene; Goals; Heart; Human Biology; In Vitro; Laboratories; Ligands; Measurement; Mediator of activation protein; Modeling; Molecular; N-terminal; Neuraxis; Peptide Hydrolases; Process; Production; Protease Domain; Publishing; Reagent; Receptor Signaling; Regulation; Rejuvenation; Role; Serum; Signal Transduction; Signaling Molecule; System; Testing; Transforming Growth Factor beta; Work; age related; aged; base; biological systems; design; experimental study; extracellular; grasp; in vitro activity; in vivo; in vivo evaluation; interest; muscle form; novel; restoration; tool

Project Summary: Growth and Differentiation Factor 11 (GDF11) and GDF8 are two closely related molecules of the larger TGFβ superfamily. While GDF8 is well known for its role in the regulation of muscle mass, evidence is now emerging that implicates GDF11 as a factor that has beneficial effects on multiple biological systems. Both GDF11 and GDF8 are tightly regulated by multiple mechanisms. Each ligand is made as a precursor with an N-terminal prodomain that remains noncovalently bound to the mature, keeping the signaling component latent until activated by Tolloid-like proteases. In addition, extracellular antagonists such as Follistatin and GASP bind and block ligand signaling. We propose that GDF11 and GDF8 are present in the serum in multiple activity states ranging from a latent form to an activated form. However, studies that investigate how the different activity states are differentially regulated are limited. We rationalize that a better understanding of these mechanisms will facilitate efforts to understand the systemic role of GDF11 and GDF8 in human biology and the aging process. To achieve this objective, we will use a combination of biochemical and molecular approaches coupled with in vitro and in vivo experiments. Our proposal is centered on three specific aims where we will (1) test the hypothesis that GDF11 and GDF8 exists in multiple ‘activity’ states that regulate a transition from a latent state to an active state, (2) test the hypothesis that the ‘net’ GDF11/GDF8 activity in serum decreases with age, and (3) test the hypothesis that GDF11 signaling and its regulation/extracellular antagonism can be decoupled. Collectively, these aims will provide a better understanding of the mechanisms of extracellular regulation of GDF11 and GDF8 and how these potentially change during the aging process. Furthermore, we expect to produce novel GDF11 and GDF8 molecules that can be used as tools to further probe the mechanisms associated with GDF11 and aging, and can also be used to restore youthful levels of GDF11 in aged animals.

项目摘要：生长和分化因子 11 (GDF11) 和 GDF8 是两个密切相关的分子 虽然 GDF8 以其在肌肉质量调节中的作用而闻名，但证据表明它是较大的 TGFβ 超家族的一部分。 现在正在出现的证据表明 GDF11 是一种对多种生物系统产生有益影响的因子。 GDF11 和 GDF8 均受到多种机制的严格调控。 N 端前结构域仍与成熟体非共价结合，保留信号成分 潜伏直至被 Tolloid 样蛋白酶激活。此外，细胞外拮抗剂如卵泡抑素和 GASP。 我们认为 GDF11 和 GDF8 在血清中以多种活性存在。 然而，研究调查了不同的活动如何发生。 我们认为，对这些机制的更好理解是有限的。 将有助于了解 GDF11 和 GDF8 在人类生物学和衰老过程中的系统作用。 为了实现这一目标，我们将结合使用生化和分子方法以及 我们的建议集中于三个具体目标，我们将（1）测试 假设 GDF11 和 GDF8 存在于多种“活动”状态，调节从潜在状态的转变 到活跃状态，(2) 检验血清中“净”GDF11/GDF8 活性随着年龄的增长而降低的假设，以及 (3)检验GDF11信号传导及其调节/细胞外拮抗作用可以解耦的假设。 总的来说，这些目标将提供对细胞外调节机制的更好理解。 GDF11 和 GDF8 以及它们在老化过程中如何潜在变化此外，我们预计会发生变化。 产生新的 GDF11 和 GDF8 分子，可用作进一步探究机制的工具 与 GDF11 和衰老相关，也可用于恢复老年动物年轻时的 GDF11 水平。