Hypercholesterolemia Impairs Stem Cell-Mediated Post-Ischemic Neovascularization

高胆固醇血症损害干细胞介导的缺血后新血管形成

基本信息

批准号：
9084611
负责人：
Louis Michael Messina
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-14 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084611
关键词：
Acquired Immunodeficiency Syndrome Affect Arterial Occlusive Diseases Arteries Attenuated Biological Assay Blood Vessels Cardiovascular Diseases Cardiovascular system Case Fatality Rates Cell physiology Cells Clinical Epidemic Epigenetic Process Functional disorder Goals Grant Health Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Impairment In Vitro Inflammatory Laboratories Limb structure Mediating Modeling Molecular Mus Peripheral Peripheral arterial disease Physiological Population Prevalence Process Research Stem cells Techniques Testing Therapeutic Tissues Transplantation Wild Type Mouse Work base cardiovascular risk factor disability genome-wide humanized mouse hypercholesterolemia in vivo in vivo Model monocyte mortality mouse model neovascularization novel novel therapeutic intervention oxidant stress preclinical study programs response stem cell differentiation transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Peripheral arterial disease is a major cause of disability and limb loss and itself carries a substantial increase in cardiovascular and all-cause mortality, such that its prevalence and case fatality rate exceeds that for AIDS. The principle physiological response to PAD is collateral artery enlargement, a form of arteriogenesis. The long-term goals of our research program are to elucidate the cellular and molecular mechanisms responsible for collateral artery enlargement and the mechanisms by which cardiovascular risk factors impair this process. Recent work in our laboratory shows that hematopoietic stem cells (HSCs) are a primary determinant of collateral artery enlargement and hypercholesterolemia impairs many of the HSC-dependent mechanisms of post-ischemic neovascularization. The Project Hypothesis of this grant is: Hypercholesterolemia-induced oxidant stress, through epigenetic mechanisms, restricts the differentiation of HSCs towards vascular cells as well as towards pro-angiogenic monocytes and rather skews their differentiation towards pro-inflammatory monocytes thereby attenuating post-ischemic neovascularization. We will test our Project Hypothesis with the following Aims: Specific Aim 1: Determine the effect of hypercholesterolemia-induced oxidant stress on HSCs differentiation into vascular cells during post-ischemic neovascularization. Specific Aim 2: Determine the effects of hypercholesterolemia-induced oxidant stress on HSC differentiation towards pro-angiogenic monocyte intermediates, CD11blow and Ly6C low populations during post-ischemic neovascularization. Specific Aim 3: Identify the epigenetic mechanisms which regulate the HSC response to hypercholesterolemia- induced oxidant stress and impairs their differentiation towards pro-angiogenic monocytes during post-ischemic neovascularization. To accomplish these aims, we will establish in vitro differentiation assays that will serve as a framework to identify and correct the epigenetic changes responsible for hypercholesterolemia-induced HSC dysfunction. In vivo transplantation models will allow us to identify epigenetic-dependent clinical consequences of hypercholesterolemia-induced HSC oxidant stress. We will also utilize these in vivo models to reverse hypercholesterolemia- induced impairments in HSC function as preclinical studies intended to evaluate new therapeutic interventions. We will also assess the impact of hypercholesterolemia on human HSC function in vitro and utilize advanced humanized mouse models for in vivo studies, thereby increasing the scientific and clinical impact of our studies. Finally, we will utilize multiple techniques to identify the epigenetic marks induced in HSCs by hypercholesterolemia on a genome-wide scale. We believe that the results of these studies will introduce novel scientific findings that will be of substantial clinical impact.

描述（由申请人提供）：周围动脉疾病是造成残疾和肢体损失的主要原因，并且本身的心血管和全因死亡率大幅增加，因此其患病率和病例死亡率超过了艾滋病。对PAD的原理生理反应是侧支动脉增大，这是动脉生成的一种形式。我们的研究计划的长期目标是阐明负责侧支动脉增大的细胞和分子机制以及心血管危险因素损害此过程的机制。我们实验室中的最新工作表明，造血干细胞（HSC）是侧支动脉增大和高胆固醇血症的主要决定因素，这会损害许多HSC后缺血性新血管形成的机制。该赠款的项目假设是：通过表观遗传学机制高胆固醇血症诱导的氧化应激，限制了HSC对血管细胞的分化以及促进血管生成单核细胞的分化，而不是将其差异化，从而偏向于促进性单细胞，从而降低了降低了衰减后神经疾病的神经疾病。我们将以以下目的测试我们的项目假设：特定目标1：确定高胆固醇血症诱导的氧化应激对HSC在缺血后新血管中分化为血管细胞的影响。具体目标2：确定高胆固醇诱导的氧化应激对HSC分化对促血管生成单核细胞中间体，CD11BLOW和LY6C低种群的影响。具体目的3：确定调节HSC对高胆固醇血症诱导的氧化剂应激的反应的表观遗传机制，并损害其在缺血后新血管化期间对促血管生成单核细胞的分化。为了实现这些目标，我们将建立体外分化测定法，该测定法将作为识别和纠正导致高胆固醇诱导的HSC功能障碍的表观遗传变化的框架。体内移植模型将使我们能够鉴定表观遗传学依赖性临床高胆固醇血症诱导的HSC氧化剂应激的后果。我们还将利用这些体内模型来逆转高胆固醇血症的HSC功能障碍，作为临床前研究，旨在评估新的治疗干预措施。我们还将评估高胆固醇血症在体外对人HSC功能的影响，并利用先进的人源性小鼠模型进行体内研究，从而增加我们研究的科学和临床影响。最后，我们将利用多种技术在全基因组量表上通过高胆固醇血症在HSC中诱导的表观遗传标记。我们认为，这些研究的结果将引入新的科学发现，这些发现将带来重大临床影响。