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Regulation of GDF11 by extracellular mechanisms

细胞外机制对 GDF11 的调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概述：生长与分化因子11 （Growth and Differentiation Factor 11, GDF11）和GDF8是两个关系密切的分子