The Role of Sema3D in Cardiac Development

Sema3D 在心脏发育中的作用

基本信息

批准号：
8698445
负责人：
Karl Degenhardt
金额：
$ 13万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-26 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698445
关键词：
Adult Advisory Committees Alkaline Phosphatase Alleles Animal Model Arrhythmia Arteries Atrial Heart Septal Defects Basic Science Binding Biochemical Biochemical Pathway Biological Assay Biological Models Biological Process Blood Vessels Candidate Disease Gene Cardiac Cardiology Cardiovascular system Child Child health care Childhood Clinical Collaborations Complex Congenital Abnormality Congenital Heart Defects Core Facility Data Defect Development Developmental Biology Developmental Process Disease Doctor of Medicine Doctor of Philosophy Embryo Embryonic Structures Endothelial Cells Ensure Environment Event Exons Faculty Genes Genetic Heart Heart Atrium Histology Human Immune Immunodeficiency and Cancer Institutes K-Series Research Career Programs Label Left atrial structure Life Lung Mediating Medicine Mentors Mentorship Missense Mutation Modeling Molecular Molecular Biology Morbidity - disease rate Mus Mutagenesis Mutant Strains Mice Mutation National Research Service Awards Neuropilin-1 Neuropilins Optics Pathogenesis Patients Pattern Pediatric Hospitals Pennsylvania Phenotype Philadelphia Physicians Plant Roots Platelet-Derived Growth Factor Receptor Play Postdoctoral Fellow Program Development Proline Protein Region Proteins Publishing Pulmonary veins Regulation Reporting Research Research Support Resources Role SECTM1 gene Science Scientist Semaphorins Serine Signal Transduction Signaling Molecule Site Stenosis Structure Structure of sinus venosus of fetus Systemic venous structure Testing Training Training Programs Tumor Angiogenesis Universities Variant Venous Work axon guidance career career development cell motility cohort congenital heart disorder design embryo tissue genetic analysis graduate student human disease in vitro Assay insight mortality mouse model mutant nervous system disorder novel pediatric department plexin professor programs receptor research study skills success tomography tool tumor progression

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for development of a research career in cardiovascular developmental biology. The candidate is a clinical associate in pediatric cardiology at the Children's Hospital of Philadelphia (CHOP), with an M.D.-Ph.D. in molecular biology. He has extended his training engaged in intensive basic science research supported by the Ruth L. Kirschstein National Research Service Award (T32), and is currently supported by the Department of Pediatrics Child Health Research Career Development Award (K12). The proposed research will enhance our understanding of congenital heart disease. It will be carried out under the mentorship of Jonathan Epstein, M.D. a recognized leader in the field of cardiac development. He is a professor of Medicine, and the scientific director of the University of Pennsylvania Cardiovascular Institute (CVI). He has mentored numerous Postdoctoral fellows and graduate students. An advisory committee of talented clinician-scientists has been assembled to offer guidance in career development and science. The environment of CHOP and the CVI provides extensive resources, collaborations, core facilities and intellectual expertise. This is an ideal training setting to develop a skill set in order to transition to an independent career as a physician-scientist. Participation in didactic courses and faculty professional development seminars will enhance the educational success of the program. Congenital heart disease (CHD) is the most common life-threatening birth defect in humans. Total or partial anomalous pulmonary venous return (TAPVR or PAPVR) are significant causes of morbidity and mortality in childhood. Moreover, the pulmonary veins are prone to stenosis, which frequently complicates the treatment of patients with TAPVR and other forms of CHD. In addition, the pulmonary veins are a frequent site of origin for atrial arrhythmias in adults, and developmental abnormalities have been proposed to be at the root of such arrhythmias. Despite these clinically compelling conditions, development of the venous pole of the heart is a relatively understudied aspect of cardiovascular development. Semaphorins represent a class of signaling molecules that are critical in various developmental processes, including axon guidance, immune regulation, tumor angiogenesis and vascular patterning. Targeted mutation of Sema3D has results in TAPVR/PAPVR in mice. These mice present a novel tool for investigating the patterning of the pulmonary veins. Sema3D binds to neuropilin-1, and this interaction will be investigated in detail. As global deletion of Sema3D has a robust phenotype in mice, it is an excellent candidate gene for CHD in humans. A Sema3D missense mutation has been found in a patient with TAPVR. The functional impact of this mutation will be investigated and additional genetic analysis of patients is underway. The data obtained in the course of the proposed research will provide insights into normal and abnormal pulmonary venous patterning, semaphorin signaling, and the genetic roots of congenital heart disease.

描述（由申请人提供）：该提案描述了一项为期五年的心血管发育生物学研究职业的培训计划。候选人是费城儿童医院（CHOP）的儿科心脏病学临床助理，并拥有M.D.-PH.D.在分子生物学中。他扩大了受到Ruth L. Kirschstein国家研究服务奖（T32）支持的强化基础科学研究的培训，目前得到儿科儿童健康研究职业发展奖（K12）的支持。拟议的研究将增强我们对先天性心脏病的理解。它将在乔纳森·爱泼斯坦（Jonathan Epstein）的指导下进行，医学博士是心脏发展领域公认的领导者。他是医学教授，宾夕法尼亚大学心血管研究所（CVI）的科学主任。他指导了许多博士后研究员和研究生。有才华的临床医生科学家的咨询委员会已经组装，以在职业发展和科学方面提供指导。 CHOP和CVI的环境提供了广泛的资源，合作，核心设施和知识专业知识。这是一个理想的培训设置，可以开发技能，以便过渡到医生科学家的独立职业。参加教学课程和教师专业发展研讨会将增强该计划的教育成功。先天性心脏病（CHD）是人类中最常见的生命的先天缺陷。总肺静脉回流（TAPVR或PAPVR）是儿童发病率和死亡率的重要原因。此外，肺静脉易于狭窄，这通常使TAPVR和其他形式的CHD患者的治疗复杂化。另外，肺静脉是成人心律不齐的常见原始部位，并且已经提出发育异常是这种心律不齐的根源。尽管有这些临床上令人信服的条件，但心脏静脉的发育是心血管发育的相对研究的方面。信号蛋白代表一类信号分子，在各种发育过程中至关重要，包括轴突引导，免疫调节，肿瘤血管生成和血管模式。 SEMA3D的靶向突变具有小鼠的TAPVR/PAPVR。这些小鼠提出了一种用于研究肺静脉模式的新工具。 SEMA3D与Neuropilin-1结合，将详细研究这种相互作用。由于SEMA3D的全球缺失在小鼠中具有强大的表型，因此它是人类中冠心病的出色候选基因。在TAPVR患者中发现了SEMA3D错义突变。将研究该突变的功能影响，并正在进行患者的其他遗传分析。在拟议的研究过程中获得的数据将提供有关正常和异常的肺静脉模式，闪存蛋白信号传导以及先天性心脏病的遗传根的见解。