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

• 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
• 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

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，含有 SH2 结构域的蛋白酪氨酸磷酸酶 Shp2 的突变与心脏病有关。大约 50% 的努南综合征 (NS) 病例和所有 LEOPARD 综合征 (LS) 病例中均发现 Shp2 基因发生突变。 NS 和 LS 具有一些共同的临床特征，包括先天性心脏缺陷，因此被视为重叠综合征。然而，LS 并不是 NS 的疾病变体； Shp2 中的 LS 相关突变催化失活，表现为显性失活，而 NS 中的 Shp2 突变催化过度活跃。这提出了一个模型，其中 LS 突变是功能丧失，而 NS 突变是功能获得。此外，大多数 LS 患者会出现肥厚型心肌病 (HCM)，这是 LS 所特有的；少数携带 Shp2 突变的 NS 患者会发展为 HCM。因此，中心假设是这两种综合征疾病之间的生化差异导致了不同的心脏缺陷。该提案将定义 Shp2 LS 突变体干扰 Erk/MAPK 通路中 Ras 上游和/或下游正信号传导事件的机制，将确定心脏中 LS 异常调节的信号传导通路，将确定心脏发生过程中需要 Shp2 的发育间隔，并将生成 LS 小鼠模型并对其进行功能分析。 候选人：Maria Kontaridis 将接受心脏病学领域的高级培训，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方面的技能。 她的资助者本杰明·尼尔 (Benjamin Neel) 是 Shp2 和小鼠遗传学方面的专家。 她的顾问小组（乔纳森·塞德曼博士、杰弗里·萨菲茨博士、刘易斯·坎特利和詹姆斯·张）都是心脏发育/病理生理学和/或信号转导方面的专家，将为她的培训和职业发展做出重大贡献。从长远来看，她计划成为学术机构的一名独立研究科学家，并指导自己的心脏发育实验室，重点研究导致先天性心脏病的信号机制（及其突变）。 相关性：这项工作将进一步明确基因突变导致心脏病的机制。 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机制来增进我们对心脏功能和发病机制的了解。 （摘要完）