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

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

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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，在整个人类中具有基本作用生物学。由于其生物学重要性，存在多种形式的调节以控制配体信号，许多特定于配体的子集。该项目将重点关注两个密切的信号和调节相关的TGF -β配体 - 生长和分化因子8（GDF8）和GDF11。在功能上，GDF8是强大的肌肉质量的负调节剂。因此，已追求对GDF8的抑制剂进行治疗诱导肌肉肥大以治疗浪费肌肉的病理。另一方面，GDF11（共享90％）对GDF8的身份，在红细胞分化中具有作用细胞生产。 GDF8和GDF11通过相似的受体都信号，并由潜伏期和细胞外拮抗剂。但是，我们的信息和机制的信息有限调节GDF8和GDF11的分子细节部分是由于缺乏描述的结构信息这些相互作用。总体目标和长期目标是了解分子机制调节GDF8和GDF11信号传导。我们将采用结构功能的方法，结构研究（x- 射线晶体学和NMR）具有结合分析和基于体外细胞的测定。观察将扩展在体内，在使用重组GDF8/11复合物的小鼠模型中。我们将追求三个特定目标将涉及（1）用其同源受体解决GDF8和GDF11的分子细节，（2）表征 GDF8和GDF11的潜在状态，并从延迟中激活它们是如何激活的，（3）确定细胞外拮抗剂喘气的结构机制，并确定拮抗剂的特异性 GDF8和GDF11。总的来说，这些目标将对调节机制有更深入的了解 GDF8和GDF11信号传导，最终可以用来促进或增加当前的治疗努力调节配体信号。