Chromosomal Rearrangements and Cardiac Candidate Genes

染色体重排和心脏候选基因

• 批准号: 7354823
• 负责人: BEVERLY S EMANUEL
• 金额: $ 47.45万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354823
• 关键词: 22q; Animal Model; Architecture; Basic Science; Biology; Candidate Disease Gene; Cardiac; Cardiology; Child; Chromosomal Rearrangement; Chromosome abnormality; Chromosomes; Clinical; Computer Simulation; Congenital Heart Defects; Cytogenetic Analysis; Cytogenetics; DNA; DNA Sequence Rearrangement; Databases; Defect; Development; Discipline; Disease; Equilibrium; Ethers; Ethyl Ether; Etiology; Fruit; Funding; Gene Mutation; Genes; Genetic; Genome; Genomics; Genus Capra; Goals; Goat; Heart; Homologous Gene; Human; Human Genome Project; Individual; Infant; Interruption; Karyotype; Lead; Location; Maps; Modeling; Molecular; Molecular Analysis; Molecular Biology; Molecular Cytogenetics; Morphogenesis; Mus; Mutation; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Phenotype; Play; Population; Positioning Attribute; Primed In Situ Labeling; Principal Investigator; Reporting; Research; Resolution; Role; Series; Specificity; Standards of Weights and Measures; Study Subject; Techniques; Tissues; Translocation Breakpoint; United States; Variant; Xenopus; Zebrafish; base; cardiogenesis; cohort; developmental genetics; dosage; interstitial; knockout gene; new technology; novel; positional cloning; programs; research study

The goal in this proposal is to use chromosomal rearrangements (CRs) occurring in children with CHDs as signposts to identify novel genes important in cardiac morphogenesis. The underlying hypothesis of this proposal is that we can identify genes critical to normal cardiac development based upon their location in relation to breakpoints of balanced translocations. Further, we hypothesize that other chromosomal changes, such as additions or interstitial deletions will assist in the identification of additional dosage sensitive genes important to cardiac development. The subjects for this study will be children who present to the SCCOR with heart defects and possibly further associated congenital anomalies. We will utilize the fruits of the Human Genome Project as well as novel technology we are developing to characterize the regions involved in the chromosomal aberrations of SCCOR patients. We hypothesize that these regions harbor genes important to normal cardiac development. We will pursue the molecular identification and analysis of cardiac candidate genes such that mutation studies can be the focus of subsequent research studies. Characterization of the candidate genes will include the delineation of their tissue, spatial and temporal expression patterns in mouse and/or Xenopus. We will isolate or identify homologues of these candidate genes in model organisms. Our specific aims include: 1) identification and characterization of CRs in patients with CHD by high-resolution cytogenetics and molecular cytogenetic analysis; 2) development of PCR-based mapping strategies using the human genomic sequence to identify translocation breakpoints (BPs); 3) Characterization of the genomic DNA from normal chromosomes at the BPs in order to identify mechanisms of rearrangement; 4) identification and characterization of genes disrupted or deleted at the translocation BPs as candidates for early cardiac morphogenesis; and 5) determination of whether mutations in the candidate genes are associated with the cardiac defect in other patients with CHD. This represents a unified program of clinical and basic research. It brings together the disciplines of clinical cardiology, clinical genetics, cytogenetics, molecular biology and developmental genetics to examine the influence of genomic variation on the etiology of CHDs in our quest to discover genes involved in fundamental pathways during early cardiogenesis.

该提案的目标是利用先心病儿童中发生的染色体重排（CR）作为路标来识别对心脏形态发生重要的新基因。该提议的基本假设是，我们可以根据基因与平衡易位断点的关系来识别对正常心脏发育至关重要的基因。此外，我们假设其他染色体变化，例如添加或间质缺失，将有助于识别对心脏发育重要的其他剂量敏感基因。这项研究的受试者是向 SCCOR 报告患有心脏缺陷以及可能进一步相关的先天性异常的儿童。我们将利用人类基因组计划的成果以及我们正在开发的新技术来表征所涉及的区域 SCCOR 患者的染色体畸变。我们假设这些区域含有对正常心脏发育很重要的基因。 我们将致力于心脏候选基因的分子鉴定和分析，使突变研究成为后续研究的重点。候选基因的表征将包括它们在小鼠和/或爪蟾中的组织、空间和时间表达模式的描绘。我们将在模式生物中分离或鉴定这些候选基因的同源物。我们的具体目标包括：1）通过高分辨率细胞遗传学和分子细胞遗传学分析来鉴定和表征先心病患者的 CR； 2) 使用PCR技术开发基于PCR的作图策略 人类基因组序列以确定易位断点 (BP)； 3) 对 BP 处正常染色体的基因组 DNA 进行表征，以确定重排机制； 4) 鉴定和表征在易位BP处被破坏或删除的基因作为早期心脏形态发生的候选基因； 5) 确定候选基因的突变是否与其他先心病患者的心脏缺陷相关。这代表了临床和基础研究的统一计划。它汇集了临床心脏病学、临床遗传学、细胞遗传学、分子遗传学等学科。 生物学和发育遗传学研究基因组变异对先心病病因的影响，以探索早期心脏发生过程中参与基本途径的基因。