Structural insight into the signaling and regulation of GDF8 and GDF11

对 GDF8 和 GDF11 信号传导和调节的结构洞察

基本信息

批准号：
9788098
负责人：
THOMAS B THOMPSON
金额：
$ 35.71万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788098
关键词：
Address Adult Affinity Anemia Binding Biochemical Biological Biological Assay Cardiovascular system Cells Cleaved cell Clinical Trials Complex Coupled Coupling Crystallization Data Development Epitopes Erythrocytes Exhibits Extracellular Protein Family Family member GDF11 gene GDF8 gene Goals Growth Factor Homeostasis Human Human Biology In Vitro Individual Ligands Modeling Molecular Muscle Muscular Atrophy N-terminal Pathology Peptide Hydrolases Phosphotransferases Predisposition Production Proteins Public Health Publishing Recombinants Regulation Research Personnel Resolution Role Serum Signal Transduction Signaling Molecule Source Specificity Structure Therapeutic Transforming Growth Factor beta Variant Walkers Wasting Syndrome X-Ray Crystallography base clinically relevant design dimer extracellular genetic regulatory protein in vivo inhibitor/antagonist insight member mouse model muscle form muscle hypertrophy receptor receptor binding targeted treatment

项目摘要

Project Summary: The TGF-β family consists of 33 individual ligands with fundamental roles throughout human biology. Due to their biological importance, multiple forms of regulation exist to control ligand signaling, many of which are specific for a subset of ligands. This project will focus on the signaling and regulation of two closely related TGF-β ligands - Growth and Differentiation Factor 8 (GDF8) and GDF11. Functionally, GDF8 is a strong negative regulator of muscle mass. As such, inhibitors to GDF8 have been pursued to therapeutically induce muscle hypertrophy in order to treat muscle-wasting pathologies. On the other hand, GDF11, which shares 90% identity to GDF8, has a role in erythrocyte differentiation where its inhibition has been shown to boost red blood cell production. Both GDF8 and GDF11 signal through similar receptors and are controlled by a combination of latency and extracellular antagonists. However, we have limited information regarding the mechanisms and molecular details that regulate GDF8 and GDF11, in part due to a lack of the structural information describing these interactions. The overall goal and long-term objective is to understand the molecular mechanisms that regulate GDF8 and GDF11 signaling. We will take a structure-function approach, coupling structural studies (X- ray crystallography and NMR) with binding analysis and in vitro cell-based assays. Observations will be extended to in vivo, in mouse models using recombinant GDF8/11 complexes. We will pursue three specific aims which will involve (1) resolving the molecular details of GDF8 and GDF11 with its cognate receptors, (2) characterizing the latent state of GDF8 and GDF11 and deciphering how they are activated from latency and (3) determining the structural mechanism of the extracellular antagonist GASP and determining how antagonism is specific for GDF8 and GDF11. Collectively, these aims will provide a deeper understanding of the mechanism that regulate GDF8 and GDF11 signaling, which can ultimately be used to facilitate or augment current therapeutic efforts to modulate ligand signaling.

项目摘要：TGF-β 家族由 33 个单独的配体组成，在整个人类中发挥着重要作用由于其生物学重要性，存在多种形式的调节来控制配体信号传导，其中许多该项目将重点关注两个密切相关的配体的信号传导和调节。相关TGF-β配体——生长和分化因子8（GDF8）和GDF11 从功能上来说，GDF8是一个很强的。因此，GDF8 抑制剂已被用于治疗诱导。另一方面，GDF11 占 90%。与 GDF8 相同，在红细胞分化中发挥作用，其抑制作用已被证明可以增加红细胞 GDF8 和 GDF11 均通过相似的受体发出信号，并由以下组合控制：然而，我们对潜伏期和细胞外拮抗剂的机制和信息有限。调节 GDF8 和 GDF11 的分子细节，部分原因是缺乏描述的结构信息这些相互作用的总体目标和长期目标是了解这些相互作用的分子机制。调节 GDF8 和 GDF11 信号传导我们将采取结构-功能方法，耦合结构研究（X-）射线晶体学和核磁共振）结合分析和体外细胞观察将得到扩展。在使用重组 GDF8/11 复合物的小鼠模型中，我们将追求三个具体目标。将涉及 (1) 解析 GDF8 和 GDF11 及其同源受体的分子细节，(2) 表征 GDF8 和 GDF11 的潜在状态并破译它们如何从延迟中被激活以及 (3) 确定细胞外拮抗剂 GASP 的结构机制并确定拮抗作用的特异性 GDF8 和 GDF11 总的来说，这些目标将提供对调节机制的更深入的理解。 GDF8 和 GDF11 信号传导，最终可用于促进或增强当前的治疗努力调节配体信号传导。