Vascular Precursors and Cell-Cell Signaling in Heart Vasculogenesis

心脏血管发生中的血管前体和细胞间信号传导

基本信息

批准号：
8864615
负责人：
Michael I. Kotlikoff
金额：
$ 38.78万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8864615
关键词：
Acute Adopted Animals Antigens Area Arrhythmia Blood Vessels Bone Marrow Bone Marrow Cells CXCR4 gene Cardiac Cardiac Myocytes Cell Communication Cell Therapy Cell Transplantation Cells Clinical Data Development Endothelial Cells Enterochromaffin Cells Fibrosis Genetic Genetic Recombination Health Heart Heart Injuries Home environment Homing Human In Vitro Incidence Infarction Inflammatory Injury Knock-out LacZ Genes Letters Ligands Maps Marrow Mesenchymal Stem Cells Mitosis Molecular Mus Myocardial Infarction Myocardial Revascularization PTPRC gene Perfusion Pericytes Population Process Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Publishing Reaction Receptor Protein-Tyrosine Kinases Recovery of Function Role Rosa Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Stem Cell Factor Stem cells Stromal Cells Therapeutic Tissues Uncertainty Vascular Endothelial Cell Vascularization angiogenesis base cadherin 5 cell injury clinically significant cytokine experience functional improvement genetic approach heart cell heart function improved in vivo injury and repair intercellular communication neovascularization paracrine precursor cell progenitor repaired research study therapeutic development vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): There is increasing evidence that recovery of function following a heart attack is markedly influenced by revascularization of the infarcted region, which influences the extent of injury, the degree of fibrosis within the infarct, post injury remodeling, and the incidence of arrhythmia. Despite the importance of revascularization, the processes underlying angiogenesis and/or vasculogenesis remain poorly understood, including the degree to which precursor cells are involved in new vessel formation, the origin of these putative precursors (e.g. bone marrow or resident adventitial cells), and the signals that govern processes such as homing, fate, and endothelial cell (EC) mitosis. This proposal examines fundamental aspects of post-infarction revascularization in vivo, exploiting recent advances in the understanding and genetic specification of vascular precursors. Our central hypothesis is that infarction triggers the expansion and differentiation of endogenous vascular precursors that are induced through key heterotypic cell-cell interactions within the perivascular niche. The proposed experiments will identify the degree to which these precursors drive revascularization, determine their developmental origin, and establish the role of the expression of c-kit, SCF, Sca1, and SDF-1α/CXCR4 signaling in this process. Defined precursor populations and terminally differentiated vascular cells (endothelial and smooth muscle) will be genetically tagged and the lineage of post-infarct nascent vascular cells examined to determine the role of angiogenesis and vasculogenesis. The role of c-kit and its ligand stem cell factor (SCF), as well as other receptor tyrosine kinases, will be examined in conditionally deleted (SCF) mice. Heterotypic signaling functions of Sca1 cells that home to infarcts and are used for cell therapy, and the importance of cardiac and marrow CXCR4 signaling will be determined in knockout or conditionally inactivated mice. These experiments will establish a conceptual framework for the understanding of ischemic revascularization of the heart, a critical step in the development of therapeutic strategies directed toward enhancing vascular repair.

描述（由申请人提供）：越来越多的证据表明，心脏病发作后的功能恢复明显受到梗塞区域血运重建的影响，这会影响损伤程度、梗塞内纤维化程度、损伤后重塑以及尽管血运重建很重要，但血管生成和/或血管发生的过程仍然知之甚少，包括前体细胞参与新血管形成的程度、心律失常的起源。这些假定的前体细胞（例如骨髓或驻留的外膜细胞），以及控制归巢、命运和内皮细胞（EC）有丝分裂等过程的信号，该提案利用了体内梗死后血运重建的基本方面。我们的中心假设是，梗塞触发内源性血管前体细胞的扩张和分化，这些内源性血管前体细胞是通过细胞内关键的异型细胞相互作用诱导的。所提出的实验将确定这些前体驱动血运重建的程度，确定其发育起源，并确定 c-kit、SCF、Sca1 和 SDF-1α/CXCR4 信号传导在此过程中的表达作用。对前体细胞群和终末分化的血管细胞（内皮细胞和平滑肌细胞）进行基因标记，并检查梗死后新生血管细胞的谱系，以确定血管生成和血管生成的作用。将在条件性缺失 (SCF) 小鼠中检查 c-kit 及其配体干细胞因子 (SCF) 以及其他受体酪氨酸激酶的作用，这些小鼠会归巢于梗塞并使用 Sca1 细胞的异型信号传导功能。对于细胞治疗，心脏和骨髓 CXCR4 信号传导的重要性将在敲除或条件灭活的小鼠中确定。这些实验将为理解缺血性血运重建建立一个概念框架。心脏，这是制定旨在增强血管修复的治疗策略的关键一步。