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病 (CHD) 是最常见的出生缺陷类型（约 1/100 活产儿），也是最常见的出生缺陷类型。已知 Ras/丝裂原激活蛋白激酶 (MAPK) 通路突变的原因。 “RASopathies”，包括努南综合征 (NS) 和伴有多发性雀斑的努南综合征 (NSML) 表现为多种临床问题，但最值得注意的是，CHD 和 NSML 患者表现出一系列症状。冠心病相关异常，如肺动脉瓣狭窄、肥厚性心肌病和房间隔大约 50% 的 NS 和 90% 的 NSML 患者存在常染色体显性突变。 PTPN11，编码含有SH2结构域的蛋白酪氨酸磷酸酶，Shp2的基因。冠心病最常见的非染色体原因，因此，了解 NS 的机制，以及后续的 NSML 将使用一套综合的方法深入了解某些形式的 CHD 的病因。我们拥有的方法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鉴定出零相关蛋白 (PZR)，一种结合 Shp2 的跨膜糖蛋白，作为一种新的靶蛋白研究发现 PZR 的酪氨酰水平异常升高。 NS 和 NSML 小鼠模型心脏中的磷酸化表明 PZR 是一个共同靶点因此，本申请的目的是 1) 定义分子决定因素。控制 PZR 的下游信号传导并确定 PZR 如何作为通用信号传导目标 NS 和 NSML，2) 测试低剂量酪氨酸激酶抑制剂破坏异常 PZR/Shp2 的功效信号传导以改善 NS 和 NSML 相关的 CHD 的发展，并且 3) 生成新型 PZR 小鼠定义 PZR 在 NS 和 NSML 相关 CHD 发展中的贡献的模型。结果将提供对 NS 和 NSML 相关 CHD 的常见机制的深入了解。将揭示 NS/NSML 相关 CHD 潜在治疗的新策略。