Project 2: Gender Dimorphism in Bone Marrow Endothelial Progenitor Cell-mediated Post-Infarct Myocardial Repair

项目2：骨髓内皮祖细胞介导的梗死后心肌修复中的性别二态性

基本信息

批准号：
10396999
负责人：
Raj Kishore
金额：
$ 43.59万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396999
关键词：
Age Area Autologous Bone Marrow Bone Marrow Involvement Cardiac Cardiovascular Diseases Cells Chimera organism Clinical Trials Complication DNA Methylation Data Disease Enzymes Epigenetic Process Equation Estrogens Experimental Animal Model Exposure to Female Gender Gonadal Hormones Gonadal Steroid Hormones Heart Injuries Heart failure Histones Homeostasis Homing Hormones In Vitro Incidence Infarction Infiltration Inflammatory Infusion procedures Injections Injury Investigation Left Ventricular Dysfunction Literature Lysine Mediating Mesenchymal Stem Cells Methylation Modality Molecular Mus Myocardial Myocardial Infarction Myocardial Ischemia Natural regeneration Neonatal Parents Pathway interactions Patients Phenotype Physiological Play Population Postmenopause Process Property Recovery of Function Reporting Research Role Severities Signal Transduction Stem cell transplant Structure Supplementation Transferase Transgenic Organisms Transplantation Treatment Efficacy Tube Woman angiogenesis base cardiac repair cardioprotection dimorphism endothelial stem cell exosome experimental study female sex hormone gain of function gender disparity histone methylation improved ischemic injury male men migration mortality myocardial injury neovascularization novel novel therapeutic intervention patient population preservation progenitor recruit repair strategy repaired reproductive response sex stem stem cell function stem cell therapy stem cells stem-like cell therapeutic evaluation tissue repair

项目摘要

Summary Cardiovascular disease (CVD) is a leading cause of mortality across the world in both men and women, however, abundant data from the literature underscore a significant disparity between men and women for the incidence and severity of CVD. It has been observed that men undergo more rapid progression of heart failure, less preservation of myocardial mass as they age, and worse age-matched cardiac contractility compared to women. Moreover, women are exposed to a lower ischemic heart complication than age- matched men both in the reproductive and postmenopausal age. These protection remain present even in neonatal, prepubescent and postmenopausal populations where there is greater homogeny of hormones between males and females indicating that although gonadal hormones do have an impact on differing incidences of disease processes among men and women, there is more to the equation. The underlying mechanisms responsible for this gender disparity beyond recognized effects of female sex hormones remain understudied. Stem cell-based therapies, particularly those employing bone marrow progenitors, have emerged as a potential novel therapeutic approach in ischemic tissue repair however patient population for available clinical trials remain disproportionately biased towards inclusion of male patients (approximately 80% male subjects). Whether gender influences EPC/stem cell reparative properties has not been well studied. Recently however, evidence has begun to emerge that gender does influence the functionality of stem/progenitor cells, although mechanisms for such functional disparity are poorly understood. Our preliminary studies indicate that bone marrow endothelial progenitor cells (EPCs) from female mice are more efficient than those from male mice in the repair and angiogenesis in ischemic heart. Additionally, our data indicates that molecular basis of this functional dimorphisms partly depends upon different epigenetic landscape in cells from different genders which appears to be independent of sex hormones including estrogen. Therefore our central hypothesis is that female derived BM- EPCs possess superior reparative properties than their male counterparts and that functional superiority of female EPCs involves both estrogen-dependent and estrogen-independent signaling and molecular mechanisms including a differential epigenetic landscape. This project aims to study, in detail, phenotypic, epigenetic and molecular basis of gender-specific differences in EPC reparative properties. This overall aim will be achieved by conducting experiments organized under the following three specific aims: 1) To determine the role of gender dimorphism on EPC -mediated post-MI repair; 2) To elucidate epigenetic mechanisms of functional disparity between male and female EPCs; and 3) To test the therapeutic efficacy of gender specific-EPC- derived exosomes as cell-free modality for post-MI repair.

概括心血管疾病（CVD）是全世界男性和女性死亡的主要原因，然而，文献中的大量数据强调了男性和女性之间在 CVD 的发生率和严重程度。据观察，男性的心脏病进展更快衰竭，随着年龄的增长，心肌质量的保存减少，以及年龄匹配的心肌收缩力较差与女性相比。此外，与同龄女性相比，女性发生缺血性心脏并发症的风险较低。与育龄和绝经后年龄的男性相匹配。即使在激素同质性较高的新生儿、青春期前和绝经后人群男性和女性之间的差异表明，尽管性腺激素确实对不同性别有影响男性和女性疾病过程的发病率，还有更多的方程式。底层的除了女性性激素的公认影响之外，造成这种性别差异的机制仍然存在待研究。基于干细胞的疗法，特别是那些使用骨髓祖细胞的疗法，已经已成为缺血组织修复的一种潜在的新型治疗方法，但患者群体现有的临床试验仍然不成比例地偏向于纳入男性患者（大约 80% 为男性受试者）。性别是否影响 EPC/干细胞修复特性尚不清楚研究过。然而最近，有证据表明性别确实会影响大脑的功能。干/祖细胞，尽管人们对这种功能差异的机制知之甚少。我们的初步研究表明，雌性小鼠的骨髓内皮祖细胞（EPC）更多在缺血心脏的修复和血管生成方面比雄性小鼠更有效。此外，我们的数据表明这种功能二态性的分子基础部分取决于不同的表观遗传不同性别细胞中的景观似乎与性激素无关，包括雌激素。因此，我们的中心假设是，雌性衍生的 BM-EPC 具有优越的修复能力。女性 EPC 的功能优势涉及到以下两个方面：雌激素依赖性和雌激素非依赖性信号传导和分子机制，包括差异表观遗传景观。该项目旨在详细研究表型、表观遗传和分子基础 EPC 修复特性的性别差异。这一总体目标将通过开展根据以下三个具体目标组织的实验：1）确定性别二态性的作用关于 EPC 介导的 MI 后修复； 2）阐明功能差异的表观遗传机制男性和女性 EPC； 3) 测试性别特异性 EPC 衍生外泌体的治疗功效心肌梗死后修复的无细胞方式。