Molecular Genetics of Carney Complex

卡尼复合物的分子遗传学

基本信息

批准号：
7643261
负责人：
CRAIG T BASSON
金额：
$ 41.46万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643261
关键词：
Ablation Adult Animal Genetics Animal Model Atrial myxoma with lentigines Benign Cardiac Cardiomyopathies Catalytic Domain Cell Differentiation process Cell Line Cells Child Clinical Contracture Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Differentiation and Growth Disease Elements Embolism Endocardial Myxoma Engineering Excision Female Fertility Fostering Genes Genetic Genetic Predisposition to Disease Genetically Engineered Mouse Heart Neoplasms Heart failure Human Human Genetics In Vitro Individual Interatrial septum Knockout Mice Lead Light Limb structure Location Male Infertility Mediating Missense Mutation Modeling Molecular Molecular Genetics Morbidity - disease rate Mus Mutation Myofibroblast Myosin ATPase Myxoma Nemaline Myopathies Neoplasms Obstruction Operative Surgical Procedures Other Genetics PKA inhibitor Pathway interactions Patients Perinatal Phenotype Pigmentation physiologic function Population Protein Isoforms Proteins Reagent Recurrence Research Research Personnel Signal Transduction Skin Skin Pigmentation Staging Stroke Symptoms Syndrome Testing Trismus Tumor-Derived Variant blastomere structure cardiogenesis cytokine genetic analysis genetic linkage analysis genetic resource heart rate variability improved in vivo male middle age mortality mouse model mutant myogenesis novel positional cloning progenitor programs tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Carney complex (CNC) is an autosomal dominant disorder in which cardiac myxomas (the most common primary cardiac tumor) occur in the setting of spotty pigmentation of the skin, extracardiac myxomas, rare nonmyxomatous tumors, and endocrinopathy. We have shown that haploinsufficient mutations of the PRKAR1A gene encoding the R1a regulatory subunit of cAMP-dependent protein kinase A cause ~2/3 of CNC. Moreover, our prkar1a +/- mouse knockout replicates several aspects of CNC including male infertility and tumorigenesis. Both murine phenotypes are rescued by genetic ablation of the Ca PKA catalytic subunit, and similar genetic modifiers may alter human tumorigenesis. We also showed that mutation of the MYH8 gene encoding perinatal myosin causes a CNC variant in which familial cardiac myxomas, spotty skin pigmentation, and endocrinopathy occur in the setting of limb contracture. The pathways in which PRKAR1A and MYH8 could intersect or synergize to contribute to heart development and to tumorigenesis remain to be established. We hypothesize that the MYH8 and PRKAR1A genes act at different stages of a molecular and cell biologic pathway to tumorigenesis. MYH8 mutations may promote the persistence into adulthood of embryonic cells that can act as tumor progenitors while PRKAR1A mutations altering the adult intracellular signal transduction milieu to stimulate the tumorigenic expansion of these progenitors. Therefore, we propose: [1] To determine requirements for perinatal myosin during cardiogenesis and tumorigenesis, [2] To determine if PRKAR1 A-dependent tumorigenesis is mediated through increased PKA activity, and [3] To identify novel genes in whom mutations cause human CNC. To achieve these aims, we will use genetically engineered chick and mouse models to determine how prkar1a, Myh8, and other genetic modifiers can regulate myogenesis, heart development and tumorigenesis. In addition, we will study the action of these genes in the myofibroblast population to determine the contribution of this lineage to CNC. Finally, we will also identify novel CNC disease genes to define additional pathogenic mechanisms intersecting with PRKAR1A and MYH8. Our research will highlight not only potential targets for treatment of cardiac myxomas and other CNC tumors but also will shed light on fundamental mechanisms regulating cell differentiation and growth that will promote improved treatments for a variety of common cardiomyopathies.

描述（由申请人提供）：卡尼复合体（CNC）是一种常染色体显性遗传疾病，其中心脏粘液瘤（最常见的原发性心脏肿瘤）发生在皮肤斑点色素沉着、心外粘液瘤、罕见的非粘液瘤和内分泌病的情况下。我们已经证明，编码 cAMP 依赖性蛋白激酶 A 的 R1a 调节亚基的 PRKAR1A 基因的单倍体不足突变导致约 2/3 的 CNC。此外，我们的 prkar1a +/- 小鼠基因敲除复制了 CNC 的多个方面，包括男性不育和肿瘤发生。这两种小鼠表型都可以通过 Ca PKA 催化亚基的基因消除来挽救，并且类似的基因修饰剂可能会改变人类肿瘤的发生。我们还表明，编码围产期肌球蛋白的 MYH8 基因突变会导致 CNC 变异，其中家族性心脏粘液瘤、斑点状皮肤色素沉着和肢体挛缩情况下发生内分泌病。 PRKAR1A 和 MYH8 交叉或协同促进心脏发育和肿瘤发生的途径仍有待确定。我们假设 MYH8 和 PRKAR1A 基因在肿瘤发生的分子和细胞生物学途径的不同阶段发挥作用。 MYH8突变可能促进可充当肿瘤祖细胞的胚胎细胞持续到成年期，而PRKAR1A突变改变成体细胞内信号转导环境，刺激这些祖细胞的致瘤性扩张。因此，我们建议：[1] 确定心脏发生和肿瘤发生过程中围产期肌球蛋白的需求，[2] 确定 PRKAR1 A 依赖性肿瘤发生是否是通过 PKA 活性增加介导的，以及 [3] 确定突变导致人类死亡的新基因。数控。为了实现这些目标，我们将使用基因工程鸡和小鼠模型来确定 prkar1a、Myh8 和其他基因修饰剂如何调节肌肉生成、心脏发育和肿瘤发生。此外，我们将研究这些基因在肌成纤维细胞群体中的作用，以确定该谱系对 CNC 的贡献。最后，我们还将鉴定新的 CNC 疾病基因，以定义与 PRKAR1A 和 MYH8 交叉的其他致病机制。我们的研究不仅将突出治疗心脏粘液瘤和其他 CNC 肿瘤的潜在靶标，还将揭示调节细胞分化和生长的基本机制，从而促进改善各种常见心肌病的治疗。