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: 7880039
• 负责人: Maria I Kontaridis
• 金额: $ 24.9万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880039
• 关键词: Address; Adult; Affect; Agonist; Alleles; Award; Binding; Binding Sites; Biochemical; Biochemistry; Biological Assay; Breeding; C-terminal; Cardiac; Cardiac Myocytes; Cardiology; Cells; Chimera organism; Clinical; Complex; Congenital Heart Defects; Correlation Studies; Data; Defect; Development; Developmental Biology; Developmental Process; Dilated Cardiomyopathy; Disease; Dominant-Negative Mutation; Embryo; Enzymes; Event; Face; Functional disorder; Gene Mutation; Genes; Genetic; Genitalia; Genotype; Goals; Grant; Growth; Heart; Heart Diseases; Heart Hypertrophy; Hypertrophic Cardiomyopathy; Institution; Knock-in Mouse; Knowledge; LEOPARD Syndrome; Lead; MAP Kinase Modules; Maps; Mediating; Mentors; Mentorship; 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; Play; Process; Proline; Protein Binding; Protein Tyrosine Phosphatase; Proteins; Publishing; Pulmonary Valve Stenosis; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Scientist; Sensorineural Hearing Loss; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stenosis; Stretching; Substrate Interaction; Syndrome; System; Tail; Testing; Time; Training; Tyrosine Phosphorylation Site; Variant; Ventricular Septal Defects; Work; base; cardiogenesis; career development; congenital heart disorder; embryonic stem cell; formycin triphosphate; gain of function; gain of function mutation; heart function; in vivo; inhibitor/antagonist; interest; loss of function; loss of function mutation; mutant; novel; post-doctoral training; postnatal; pressure; receptor; response; retinal rods; skeletal; skills; src Homology Region 2 Domain; transcription factor; transmission process

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 -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.

摘要：最近，含有 SH2 结构域的蛋白酪氨酸磷酸酶 Shp2 发生突变， 与心脏病有关。 Shp2 被确定为 -50% 的 Noonan 病例中的突变基因 综合征 (NS) 和所有 LEOPARD 综合征 (LS) 病例。 NS 和 LS 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 不是 NS 疾病变体； Shp2 中 LS 相关突变催化失活，表现为显性突变 阴性，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，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 特有的；很少有携带 Shp2 突变的 NS 患者出现 肥厚型心肌病。因此，中心假设是这两种综合征之间的生化差异 疾病会引起明显的心脏缺陷。该提案将定义 Shp2 LS 的机制 突变体干扰 Erk/MAPK 中 Ras 上游和/或下游的正信号传导事件 途径，将确定心脏中 LS 异常调节的信号传导途径，将识别 心脏发生过程中需要 Shp2 的发育间隔，并且会生成并发挥功能 分析 LS 小鼠模型。候选人：玛丽​​亚·康塔里迪斯将接受以下领域的高级培训 心脏病学并将进一步发展分子和发育生物学、生物化学和小鼠方面的技能 该奖项的指导阶段的遗传学。她的资助者本杰明·尼尔 (Benjamin Neel) 是 Shp2 领域的专家， 小鼠遗传学。她的顾问小组（乔纳森·塞德曼博士、杰弗里·萨菲茨、刘易斯·坎特利和詹姆斯 Chang），所有心脏发育/病理生理学和/或信号转导领域的专家都将做出贡献 对她的培训和职业发展有重大意义。从长远来看，她计划成为一个独立的人 学术机构的研究科学家，并指导她自己的心脏发育实验室， 强调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的方法增进我们对心脏功能和发病机制的了解。 了解介导这些过程的基本信号机制。