Mechanisms of Pulmonary Vein Development

肺静脉发育机制

基本信息

批准号：
7211350
负责人：
STEVEN B BLEYL
金额：
$ 13.47万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7211350
关键词：
4q12 Abbreviations Affect Alleles Apoptotic Arts Biological Assay Cardiac Caring Cell Cycle Cell Proliferation Cell Survival Cells Chick Embryo Chromosomes Clinical Complex Congenital Abnormality Congenital Heart Defects Data Defect Development Development Plans Embryo Embryonic Development Enhancers Faculty Family Gene Proteins Genes Genetic Growth Factor Receptors Heart Heart Atrium Histology Human Human Genetics Imatinib Infant Mortality Isomerism K-Series Research Career Programs Label Left Left atrial structure Life Ligands Live Birth Lung Maps Mediating Mentors Mesenchymal Mesenchyme Mesoderm Microarray Analysis Molecular Genetics Morphology Mus Mutant Strains Mice Mutation Names Organogenesis Pathway interactions Pattern Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor alpha Receptor Point Mutation Process Proteins Pulmonary veins Regulation Research Research Personnel Resources Role Side Signal Transduction Signaling Molecule Structure Testing Thinking Training Venous abstracting career cell behavior design dimer dosage genetic linkage analysis migration mutant platelet-derived growth factor A platelet-derived growth factor C programs receptor research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Abnormal cardiac inflow tract remodeling can result in total anomalous pulmonary venous return (TAPVR), a life-threatening congenital heart defect. My human genetic studies and my preliminary expression and functional data in chick and mouse embryos suggest that PDGF-signaling is required for inflow tract remodeling and correct pulmonary venous connection. Asymmetric accumulation of cells in the heart stalk is thought to be important for inflow tract and pulmonary vein (PV) development. My data in chick show that Pdgfra and its ligand Pdgfa are expressed in mesenchyme on opposite sides of the heart stalk during PV formation and later around the PV as it matures. I hypothesize that asymmetric expression of PDGF signaling molecules in the heart stalk is required for normal inflow tract and PV development. The transcription factor PITX2 is a key player in asymmetric organogenesis. Mice lacking asymmetric expression of PITX2 have TAPVR. I hypothesize that downstream targets of PITX2 in the heart stalk, likely to include PDGF-signaling molecules, mediate inflow tract remodeling and PV development. My long-term objective is to understand the genetic pathways that regulate inflow tract remodeling and the pulmonary venous connection to the left atrium. I propose the following specific aims 1. Characterize PDGF-signaling in the mouse heart stalk: define the temporal and spatial expression patterns of the PDGF receptors and ligands in the developing mouse heart stalk; determine the requirement of PDGF-signaling in heart stalk patterning and PV development using PDGFRA deficient mouse mutants; examine the cellular mechanisms underlying the leftward shift of the PV. 2. Identify PITX2-regulated genes during mouse inflow tract remodeling: define the expression pattern of PDGF-signaling molecules in Pitx2 mutants lacking an asymmetric enhancer; use these Pitx2AASE mutants to identify PITX2-regulated genes in the inflow tract and heart stalk by microarray analysis. A well structured career development plan, extensively supported with institutional resources and internationally known mentors, has been designed to allow me to transition during the tenure of the K award to an independent tenure-track faculty investigator. Thus, I will receive the necessary training both to direct an active research program and provide state-of-the-art clinical care. (End of Abstract)

描述（由申请人提供）：异常心脏流入道重塑会导致总异常肺静脉回流（TAPVR），这是一种危及生命的先天性心脏缺陷。我的人类遗传研究以及我在雏鸡和小鼠胚胎中的初步表达和功能数据表明，流入道和正确的肺静脉连接需要PDGF信号。心脏茎中细胞的不对称积累被认为对于流入道和肺静脉（PV）发育很重要。我在Chick中的数据表明，PDGFRA及其配体PDGFA在PV形成期间在心脏茎的相对侧的间充质表达，随后在PV成熟时。我假设正常流入道和PV发育需要PDGF信号分子的不对称表达。转录因子PITX2是不对称器官发生的关键参与者。缺乏PITX2不对称表达的小鼠具有TAPVR。我假设心脏茎中Pitx2的下游靶标可能包括pDGF信号分子，介导流入道和PV的发展。我的长期目标是了解调节流动区重塑的遗传途径以及与左心房的肺静脉连接。我提出了以下特定目的1。表征小鼠心脏茎中的pDGF信号：定义发育中的小鼠心脏茎中PDGF受体和配体的时间和空间表达模式；使用PDGFRA缺乏小鼠突变体在心脏茎模式和PV发育中确定PDGF信号的需求；检查PV向左移位的基础机制。 2。在小鼠流入道重塑过程中识别PITX2调节的基因：定义缺乏不对称增强子的PITX2突变体中PDGF信号分子的表达模式；通过微阵列分析，使用这些PITX2Aase突变体在流入道和心脏茎中鉴定PITX2调节的基因。一项结构良好的职业发展计划，在机构资源和国际知名的导师方面得到了广泛的支持，旨在使我在K奖的任期期间过渡到独立的终身教师调查员。因此，我将获得必要的培训，以指导主动研究计划并提供最先进的临床护理。（抽象的结尾）