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

• 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
• 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

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率的主要原因， 但是，文献中的大量数据强调了男性和女性之间的显着差异 CVD的发病率和严重程度。已经观察到男人经历了更快的心脏进展 失败，较少的心肌质量随着年龄的增长和年龄匹配的心脏收缩性较差 与女性相比。此外，女性与年龄相比，女性暴露于低缺血性心脏并发症 在生殖和绝经后年龄匹配的男人。这些保护仍然存在于 新生儿，青春期前和绝经后种群，激素的同质性较高 在男性和女性之间表明，尽管性腺激素确实对不同 男女疾病过程的发生率，方程更多。基础 导致这种性别差异的机制超出了女性性激素的公认影响 研究了。基于干细胞的疗法，尤其是使用骨髓祖细胞的疗法，具有 在缺血性组织修复中成为一种潜在的新型治疗方法，但是患者人群 可用的临床试验仍然不成比例地包含男性患者（大约 80％男性受试者）。性别是否影响EPC/干细胞修复特性尚不很好 研究。然而，最近，有证据表明性别确实会影响 茎/祖细胞，尽管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 在缺血性心脏的修复和血管生成中，雄性小鼠的高效。此外，我们的数据 表明该功能二态性的分子基础部分​​取决于不同的表观遗传学 来自不同性别的细胞中的景观似乎独立于性激素，包括 雌激素。因此，我们的中心假设是女性衍生的BM- EPC具有优越的修复 比男性的特性，女性EPC的功能优势既涉及 雌激素依赖性和雌激素独立的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，表观遗传学和分子基础 EPC修复特性的性别特异性差异。这一总体目标将通过进行 以下三个特定目的组织的实验：1）确定性别二态性的作用 在EPC介导的MI后修复上； 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派生外泌体的治疗功效 无细胞的模态用于MI后修复。