HEMATOPOIETIC STEM CELLS IN CARDIOVASCULAR REGENERATIVE MEDICINE

造血干细胞在心血管再生医学中的应用

• 批准号: 7720834
• 负责人: Richard P Visconti
• 金额: $ 17.17万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720834
• 关键词: Acute; Behavior; Biochemical; Biological; Bone Marrow; Cardiac; Cardiovascular system; Cells; Cessation of life; Chronic; Cicatrix; Collagen Type I; Computer Retrieval of Information on Scientific Projects Database; DDR2 gene; Engraftment; Fibroblasts; Funding; Grant; Hematopoietic stem cells; Home environment; Infarction; Institution; Messenger RNA; Molecular; Mus; Myocardial Infarction; Myocardium; Numbers; Population; Proteins; Rate; Regenerative Medicine; Research; Research Personnel; Resources; Signal Transduction; Source; Tensile Strength; Testing; Tissues; Transplantation; United States National Institutes of Health; Ventricular Remodeling; Wild Type Mouse; base; in vivo; periostin; protein expression; research study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our preliminary studies, using lineage-marked (EGFP+) bone marrow, demonstrate that there is hematopoietic stem cell contribution to the cardiac fibroblast population, based on our findings that a sub-population of HSC-derived cells express DDR2 and synthesize collagen type I in the infarcted myocardium. These HSC-derived cells, which densely populate the damaged myocardium, could possibly be used to modulate the degree of pathological remodeling in the post-infarction myocardium. Proposed studies will define the molecular and biochemical contribution of HSC-derived cardiac fibroblasts to post-infarction scar formation and cardiac function, and compare these cell biological behaviors to those of resident cardiac fibroblasts. Proposed experiments will also examine the effects of modulation of numbers of HSC-derived cells that engraft into the myocardium in response to infarction as well as the effects of modulation of periostin signaling on the fibroblastic differentiation of HSC-derived cells that home to the infarct zone. There are three aims: a) to test the hypothesis that HSC-derived fibroblasts (HSC-f) participate in post-infarction ventricular remodeling, we will perform comprehensive analysis of expression of post-infarction fibroblast-specific mRNA and protein, rates of proliferation and death, and lineage analysis of HSC-fs. b) to test the hypothesis that modulation of HSC-f engraftment into the infarcted cardiac tissue influences post-infarction cardiac function and pathological remodeling, analysis of cardiac function, tensile strength, and tissue remodeling will be performed to evaluate the effects of myocardial infarction combined with modulation of bone marrow mobilization in HSC-transplanted mice. c) to test the hypothesis that the matricellular protein periostin is an active effector of fibroblastic differentiation by HSC-derived cells that engraft into the post-infarction scar. Fibroblast-specific mRNA and protein expression, in vivo fibrogenic response and cardiac functional analyses will be performed in wild-type mice engrafted with PN-/- bone marrow HSCs (vs. wild type HSCs) and subjected to MI to determine the effects of modulation of PN expression on acute and chronic pathological remodeling of the myocardium.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的初步研究，使用谱系标记（EGFP+）的骨髓，证明有造血干细胞的贡献，心脏成纤维细胞群体，基于我们的研究结果，HSC衍生的细胞亚群表达DDR2和合成胶原蛋白I型在梗死心肌。这些HSC衍生的细胞密集地分布在受损的心肌中，可能用于调节梗死后心肌的病理性重构程度。 拟议的研究将确定HSC衍生的心脏成纤维细胞对梗死后瘢痕形成和心脏功能的分子和生化贡献，并将这些细胞生物学行为与常驻心脏成纤维细胞的生物学行为进行比较。提出的实验还将检查响应于梗死而移植到心肌中的HSC衍生细胞的数量的调节的影响，以及骨膜蛋白信号传导对归巢到梗死区的HSC衍生细胞的成纤维细胞分化的调节的影响。有三个目标： a）、 为了验证HSC衍生的成纤维细胞（HSC-f）参与梗死后心室重构的假设，我们将对梗死后成纤维细胞特异性mRNA和蛋白的表达、增殖和死亡率以及HSC-f的谱系分析进行综合分析。 B） 为了检验HSC-f移植到梗塞心脏组织中的调节影响梗塞后心脏功能和病理性重塑的假设，将进行心脏功能、抗张强度和组织重塑的分析，以评价心肌梗塞与骨髓动员的调节组合在HSC移植小鼠中的作用。 c）、 以检验以下假设：基质细胞蛋白骨膜蛋白是移植到梗塞后瘢痕中的HSC衍生细胞的成纤维细胞分化的活性效应物。将在移植有PN-/-骨髓HSC（与野生型HSC相比）并经历MI的野生型小鼠中进行成纤维细胞特异性mRNA和蛋白质表达、体内纤维化反应和心脏功能分析，以确定PN表达调节对心肌急性和慢性病理性重塑的影响。