Regulation of GDF11 by extracellular mechanisms

细胞外机制对 GDF11 的调节

• 批准号: 10689719
• 负责人: THOMAS B THOMPSON
• 金额: $ 54.1万
• 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/10689719
• 关键词: Affect; Age; Aging; Animals; Binding; Biochemical; Biological; Biological Process; Buffers; Central Nervous System; Clinical; Clinical Trials; Complex; Coupled; Cues; Development; Engineering; Erythrocytes; Extracellular Protein; Family; Family member; Follistatin; GDF11 gene; GDF8 gene; Goals; Growth Factor; Heart; Human Biology; In Vitro; Laboratories; Ligand Binding; Ligands; Measurement; Mediator; Modeling; Molecular; N-terminal; Peptide Hydrolases; Process; Production; Protease Domain; Publishing; Rationalization; Reagent; Receptor Signaling; Regulation; Rejuvenation; Role; Serum; Signal Transduction; Signaling Molecule; System; Testing; Transforming Growth Factor beta; Work; age related; aged; antagonist; biological systems; cell growth regulation; design; experimental study; extracellular; grasp; in vitro activity; in vivo; in vivo evaluation; interest; morphogens; 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 尽管GDF8以其在调节肌肉质量中的作用而闻名 现在正在出现，将GDF11作为对多种生物系统具有有益影响的因素。 GDF11和GDF8均受多种机制的严格调节。每个配体都是作为前体的 N末端prodomain，该末端依赖于成熟的成熟，保持信号分量 潜在直至被肉眼样蛋白酶激活。此外，细胞外拮抗剂，例如卵泡蛋白和喘气 绑定并阻止配体信号传导。我们建议在多种活动中的血清中存在GDF11和GDF8 状态从潜在形式到激活形式。但是，研究了不同活动的研究 州的规范不同受到限制。我们合理地对这些机制有更好的理解 将促进努力了解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，我们将使用生化和分子方法的组合， 体外实验。我们的建议集中于三个特定目标，我们将在其中测试 假设GDF11和GDF8存在于多个“活动”状态，这些状态从潜在状态进行过渡 到活跃状态，（2）检验以下假设：血清中的“净” GDF11/GDF8活性随着年龄的增长而下降，并且 （3）检验了可以将GDF11信号传导及其调节/细胞外拮抗作用的假设解耦。 总的来说，这些目标将更好地理解对细胞外调节的机制 GDF11和GDF8以及这些在衰老过程中的潜在变化。此外，我们希望 生产新型的GDF11和GDF8分子，可以用作进一步探测机制的工具 与GDF11和衰老相关，还可以用于恢复老年动物中年轻水平的GDF11。