Medhanism of EPC Dysfunction in the SS: Quantity over Quality

SS 中 EPC 功能障碍的机制：数量重于质量

基本信息

批准号：
9357381
负责人：
Eric c Exner
金额：
$ 4.61万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2020-08-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9357381
关键词：
Affect Aging Angiotensin II Animal Model Animals Antibodies Autologous Biological Assay Bone Marrow Cell Culture System Cell Therapy Cell membrane Cell physiology Cell-Mediated Cytolysis Cells Chromosomes Chromosomes, Human, Pair 13 Clinical Trials Competence Computer Simulation Data Development Diabetes Mellitus Diabetic Neuropathies Disease Dose Exhibits Functional disorder Genes Goals Heart Hindlimb Hormones Human Hypertension Impairment In Vitro Infusion procedures Injectable Killer Cells Knock-out Ligand Binding Limb structure Longevity Masks Mediating Membrane Membrane Proteins Microvascular Dysfunction Modeling Molecular Conformation Mononuclear Myocardial Infarction NK Cell Activation Natural Increases Natural Killer Cells Natural regeneration Organ Pathologic Patients Peripheral arterial disease Physiological Population Predisposition Protein Isoforms Proteome Rat Strains Rattus Rattus norvegicus Receptor Cell Research Role Small Interfering RNA Stem cells Stroke Testing Therapeutic Time Tissues Transcript Treatment Efficacy adult stem cell angiogenesis base cardiovascular risk factor consomic cytotoxicity in vivo in vivo Model killings knock-down mRNA Expression overexpression peripheral blood protein structure receptor repaired restoration salt sensitive hypertension stem cell therapy vector-induced

项目摘要

Project Summary Endothelial progenitor cells (EPCs) are adult stem cells with roles in angiogenesis and endothelial function. Human and animal studies suggest that autologous stem cell therapy using an EPC enriched population of cells can be therapeutic in diseases such as hypertension, myocardial infarction, stroke, and diabetes. However, EPCs from diseased and aging hosts show decreases in number and function that are likely to compromise therapeutic efficacy, thus masking the potential of EPC based therapy. The objective of this study is to determine the mechanism of impaired angiogenic competency of EPCs in an animal model of EPC dysfunction. In the proposed animal model, the SS/MCWi (SS) rat, EPC competency and longevity is impaired in vivo but rescued in vitro. We have observed an increase in the natural killer (NK) cell receptor 2B4 (CD244) on the membrane of SS EPCs and an increase in killing of SS EPCs by SS NK cells. We hypothesize that increased expression of CD244 on the EPC membrane leads to increased NK cell mediated destruction of SS EPCs in vivo, which compromises their ability to induce angiogenesis. We will use an in vitro cytotoxicity assay and an in vivo model of hind-limb angiogenesis to test the effects of CD244 knockdown and NK cell depletion on NK cell mediated destruction and angiogenic competency of SS EPCs. We will also assess the physiological impact of the various observed CD244 transcript sequences in an in vitro cell culture system. Because we have previously shown that low-dose angiotensin II (AngII) restores angiogenesis in SS rats and angiogenic competency in SS bone marrow mononuclear cells, we will assess the effects of AngII on the angiogenic competency, CD244 expression, and NK cell mediated cytotoxicity of SS EPCs.

项目概要内皮祖细胞 (EPC) 是成体干细胞，在血管生成和内皮细胞中发挥作用功能。人类和动物研究表明，使用 EPC 富集的自体干细胞治疗细胞群可以治疗高血压、心肌梗塞、中风等疾病糖尿病。然而，来自患病和衰老宿主的 EPC 数量和功能均有所下降，可能会损害治疗效果，从而掩盖基于 EPC 的治疗的潜力。的目标本研究旨在确定动物模型中 EPC 血管生成能力受损的机制 EPC功能障碍。在所提出的动物模型中，SS/MCWi (SS) 大鼠的 EPC 能力和寿命为在体内受损但在体外得到拯救。我们观察到自然杀伤 (NK) 细胞受体 2B4 有所增加 (CD244) 存在于 SS EPC 的膜上，并且 SS NK 细胞对 SS EPC 的杀伤作用增加。我们假设 EPC 膜上 CD244 表达增加导致 NK 细胞增加介导体内 SS EPC 的破坏，从而损害其诱导血管生成的能力。我们将使用体外细胞毒性测定和后肢血管生成的体内模型来测试 CD244 敲低和 NK 细胞耗竭对 NK 细胞介导的 SS 破坏和血管生成能力的影响 EPC。我们还将评估各种观察到的 CD244 转录序列的生理影响体外细胞培养系统。因为我们之前已经证明，低剂量的血管紧张素II（AngII）可以恢复 SS 大鼠的血管生成和 SS 骨髓单核细胞的血管生成能力，我们将评估 AngII对SS的血管生成能力、CD244表达和NK细胞介导的细胞毒性的影响 EPC。