Molecular Pathogenesis of the Cardiomyogenic Defects in LEOPARD Syndrome

LEOPARD 综合征心肌源性缺陷的分子发病机制

基本信息

批准号：
7251039
负责人：
Maria I Kontaridis
金额：
$ 8.8万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251039
关键词：
Affect Alleles Award Binding Biochemical Biochemistry C-terminal Cardiac Cardiac Myocytes Cardiology Cells Clinical Complex Congenital Heart Defects Data Defect Development Developmental Biology Developmental Process Dilated Cardiomyopathy Disease Dominant-Negative Mutation Embryo Enzymes Event Face Functional disorder Gene Mutation Genes Genetic Genitalia Goals Growth Heart Heart Diseases Hypertrophic Cardiomyopathy Institution Knock-in Mouse Knowledge LEOPARD Syndrome Lead MAP Kinase Modules Maps Mediating Mentors Modeling Molecular Molecular Conformation Multiple Lentigines Mus Mutate Mutation Myocardial N-terminal Noonan Syndrome Orbital separation excessive PTPN11 gene Pathogenesis Pathway interactions Patients Penetrance Phase Phenotype Phosphoric Monoester Hydrolases Phosphorylation Site Phosphotransferases Phosphotyrosine Process Proline Protein Tyrosine Phosphatase Proteins Publishing Pulmonary Valve Stenosis Receptor Protein-Tyrosine Kinases Regulation Research Research Personnel Scientist Sensorineural Hearing Loss Signal Pathway Signal Transduction Signaling Molecule Site Skeletal system Stenosis Stretching Syndrome System Tail Testing Training Tyrosine Phosphorylation Site Variant Ventricular Septal Defects Work abstracting base cardiogenesis career congenital heart disorder gain of function gain of function mutation in vivo interest loss of function mutation mutant postnatal programs receptor skills src Homology Region 2 Domain transcription factor

项目摘要

DESCRIPTION (provided by applicant): SUMMARY: Recently, mutations in the SH2 domain-containing protein tyrosine phosphatase Shp2, have been implicated in cardiac disease. Shp2 was identified as the gene mutated in approximately 50% of cases of Noonan Syndrome (NS) and all cases of LEOPARD Syndrome (LS). NS and LS share several clinical features, including congenital heart defects, and, as such, were viewed as overlap syndromes. However, LS is NOT a disease variant of NS; LS-associated mutations in Shp2 are catalytically inactive and behave as dominant negatives, whereas Shp2 mutations in NS are catalytically hyperactive. This proposes a model in which LS mutations are loss-of-function and NS mutations are gain-of-function. Moreover, most LS patients develop a hypertrophic cardiomyopathy (HCM), which is unique to LS; few NS patients with Shp2 mutations develop HCM. The central hypothesis, therefore, is that biochemical differences between these two syndromic disorders give rise to distinct cardiac defects. This proposal will define the mechanism(s) by which Shp2 LS mutants interfere with positive signaling events upstream and/or downstream of Ras in the Erk/MAPK pathway, will determine the signaling pathways that are aberrantly regulated by LS in the heart, will identify the developmental interval in which Shp2 is required during cardiogenesis, and will generate and functionally analyze a murine model of LS. CANDIDATE: Maria Kontaridis will receive advanced training in the field of cardiology and will further develop skills in molecular and developmental biology, biochemistry, and mouse genetics during the mentored phase of this award. Benjamin Neel, her sponsor, is an expert in Shp2 and mouse genetics. Her advisory panel (Drs. Jonathan Seidman, Jeffrey Saffitz, Lewis Cantley and James Chang), all experts in cardiac development/pathophysiology and/or signal transduction, will contribute substantially to her training and career development. Long-term, she plans to become an independent research scientist at an academic institution and to direct her own lab in cardiac development, with an emphasis on the signaling mechanisms (and mutations therein) that lead to congenital heart disease. RELEVANCE: This work will further define the mechanisms by which genetic mutations lead to cardiac disease. These findings will advance our knowledge of cardiac function and pathogenesis through better understanding of the fundamental signaling mechanisms that mediate these processes. (End of Abstract)

描述（由申请人提供）：摘要：最近，含SH2结构域的蛋白酪氨酸磷酸酶SHP2中的突变已与心脏病有关。 SHP2被鉴定为在大约50％的Noonan综合征（NS）和所有豹综合征病例（LS）的基因中突变的基因。 NS和LS具有多种临床特征，包括先天性心脏缺陷，因此被视为重叠综合征。但是，LS不是NS的疾病变异。 SHP2中与LS相关的突变是催化性无活性的，表现为主要负面因素，而NS中的SHP2突变是催化过度活跃的。这提出了一个模型，其中LS突变是功能丧失，而NS突变是功能收益。此外，大多数LS患者都会发展出肥厚的心肌病（HCM），该心肌病是LS独有的。很少有NS SHP2突变患者出现HCM。因此，中心假设是这两种综合症疾病之间的生化差异会导致不同的心脏缺陷。该提案将定义SHP2 LS突变体在ERK/MAPK途径中RAS上游和/或下游的正面信号事件的机制，将确定由心脏中LS中LS异常调节的信号通路，将确定SHP2在哪个SHP2中确定在哪个shp2的过程中需要在哪个shp2中生成和分析。候选人：Maria Kontaridis将在心脏病学领域接受高级培训，并将在该奖项的指导阶段进一步发展分子和发育生物学，生物化学和小鼠遗传学的技能。她的赞助商本杰明·尼尔（Benjamin Neel）是SHP2和小鼠遗传学的专家。她的咨询小组（Jonathan Seidman博士，Jeffrey Saffitz，Lewis Cantley和James Chang博士）是心脏发展/病理生理学和/或信号转变的所有专家，将为她的培训和职业发展做出重大贡献。长期，她计划成为学术机构的独立研究科学家，并指导自己的心脏发展实验室，重点是导致先天性心脏病的信号传导机制（及其中的突变）。相关性：这项工作将进一步定义遗传突变导致心脏的机制疾病。这些发现将通过更好地理解介导这些过程的基本信号传导机制来提高我们对心脏功能和发病机理的了解。（抽象的结尾）