Signaling by Shp2 mutants in RASopathies

RASopathies 中 Shp2 突变体的信号传导

基本信息

批准号：
9889163
负责人：
Anton M Bennett
金额：
$ 56.13万
依托单位：
YALE UNIVERSITY
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：
2018-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889163
关键词：
Atrial Heart Septal Defects Binding Biochemistry Birth Cardiac Cardiac development Cardiomyopathies Cellular biology Cessation of life Clinical Complex Congenital Abnormality Congenital Heart Defects Dasatinib Data Defect Development Disease Dose Etiology Exhibits FDA approved Genetic Glycoproteins Goals Heart Heart Abnormalities Hypertrophic Cardiomyopathy Incidence Internet Knock-in Mouse LEOPARD Syndrome Lead Live Birth MPZL1 gene Mediating Membrane Mental Retardation Mitogen-Activated Protein Kinases Modeling Molecular Multiple Lentigines Mus Musculoskeletal Mutant Strains Mice Mutate Mutation Myocardial dysfunction Neck Noonan Syndrome Orbital separation excessive PTPN11 gene Pathogenesis Pathway interactions Patients Pharmacology Phosphoric Monoester Hydrolases Phosphorylation Physiological Play Protein Tyrosine Phosphatase Proteins Proteomics Pulmonary valve structure Role SRC gene Signal Pathway Signal Transduction Specificity Stenosis Syndrome Testing Therapeutic Tissues Tyrosine Kinase Inhibitor Zebrafish autosomal dominant mutation cardiogenesis congenital heart disorder defined contribution efficacy testing genetic analysis heart function improved insight kinase inhibitor mouse model mutant novel novel strategies phosphoproteomics protein complex recruit scaffold src Homology Region 2 Domain src-Family Kinases treatment strategy

项目摘要

Abstract/Project Summary Congenital heart defects (CHDs) are the most common type of birth defect (~1/100 live births) and the major cause of birth-related deaths. Mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway known as “RASopathies” that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) manifest in a variety of clinical problems but most notably, CHDs. NS and NSML patients exhibit a range of CHD-related anomalies such as pulmonic valve stenosis, hypertrophic cardiomyopathy and atrial septal defects. Approximately, 50% of NS and 90% of NSML patients have autosomal dominant mutations in PTPN11, the gene encoding the SH2 domain-containing protein tyrosine phosphatase, Shp2. NS represents the most common non-chromosomal cause of CHD. Therefore, understanding the mechanisms of NS, and subsequently NSML, will provide insight into the causation of some forms of CHD. Using an integrated set of approaches that include phospho proteomics, zebrafish genetics, biochemistry and cell biology we have identified protein zero-related (PZR), a transmembrane glycoprotein that binds Shp2, as a novel target protein involved in heart development. PZR was identified to be aberrantly increased in its levels of tyrosyl phosphorylation in the heart of mouse models of both NS and NSML suggesting that PZR is a common target of these RASopathies. Therefore, the aims of this application are to 1) define the molecular determinants governing downstream signaing of PZR and to determine how PZR serves as a common signaling target for NS and NSML, 2) test the efficacy of low-dose tyrosine kinase inhibitors to disrupt aberrant PZR/Shp2 signaling to ameliorate the development of NS- and NSML-related CHD and 3) generate novel PZR mouse models to define the contribution of PZR in the development of NS and NSML-related CHD. Collectively, these results will provide insight into common mechanisms that underlie both NS and NSML-related CHD. Finally, novel strategies for the potential treatment of NS/NSML-associated CHD will be uncovered.

摘要/项目摘要先天性心脏缺陷（CHD）是最常见的先天缺陷类型（〜1/100 Live Births），主要类型与出生有关的原因。 RAS/有丝分裂原激活蛋白激酶（MAPK）途径的突变已知作为包括Noonan综合征（NS）和Noonan综合征的“ Rasopathies”（NSML）在各种临床问题中表现出来，但最著名的是CHD。 NS和NSML患者表现出一系列与CHD相关的异常，例如肺动脉瓣狭窄，肥厚性心肌病和心房间隔缺陷。大约有50％的NS和90％的NSML患者具有常染色体显性突变 PTPN11，编码含SH2结构域的蛋白酪氨酸磷酸酶SHP2的基因。 NS代表冠心病最常见的非染色体原因。因此，了解NS的机制以及随后，NSML将为某些形式的CHD原因提供洞察力。使用一组集成的包括磷酸蛋白质组学，斑马鱼遗传学，生物化学和细胞生物学的方法确定的蛋白质零相关（PZR），一种结合SHP2的跨膜糖蛋白，作为一种新型靶蛋白参与心脏发展。 PZR被确定为其酪酶水平异常增加 NS和NSML小鼠模型中心的磷酸化表明PZR是常见的靶标这些ras病。因此，该应用的目的是1）定义分子确定剂管理PZR的下游签名并确定PZR如何用作通用信号目标 NS和NSML，2）测试低剂量酪氨酸激酶抑制剂的效率破坏异常PZR/SHP2 信号调解NS和NSML相关的冠心病的发展，3）生成新型PZR小鼠定义PZR在NS和NSML相关CHD开发中的贡献的模型。总的来说，这些结果将提供有关NS和NSML相关CHD构成的常见机制的洞察力。最后，将发现NS/NSML相关CHD潜在治疗的新型策略。