MSC-derived microvesicles in metabolic syndrome and renovascular disease

间充质干细胞衍生的微泡在代谢综合征和肾血管疾病中的作用

• 批准号: 9231450
• 负责人: Lilach O Lerman
• 金额: $ 68.82万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231450
• 关键词: Address; Adipose tissue; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Basic Science; Blood Pressure; Cell Therapy; Cell physiology; Cholesterol; Chronic; Chronic Kidney Failure; Clinical; Clinical Medicine; Development; Diabetes Mellitus; Disease; Dose; Dyslipidemias; Effectiveness; Epidemic; Evolution; Family suidae; Fatty acid glycerol esters; Functional Imaging; Functional disorder; Genetic Transcription; Glucose; Goals; Health Professional; Human; Hypertension; Imaging Device; Imaging Techniques; In Vitro; Inflammation; Injectable; Injection of therapeutic agent; Injury; Insulin Resistance; Intervention; Ischemia; Kidney; Kidney Diseases; Ligands; Link; Magnetic Resonance Imaging; Mediating; Membrane; Mesenchymal Stem Cells; Messenger RNA; Metabolic Diseases; Metabolic syndrome; Methods; MicroRNAs; Microcirculation; Mission; Modeling; Molecular Analysis; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Outcome; Parents; Patients; Pattern; Physiological; Prevalence; Property; Reagent; Regenerative Medicine; Renal function; Resolution; Risk; Signal Transduction; Stem cells; Structure; Testing; Therapeutic; Translational Research; Tubular formation; X-Ray Computed Tomography; base; cardiovascular risk factor; clinical application; clinically relevant; extracellular; hemodynamics; human disease; improved; in vivo; innovation; kidney vascular structure; microvesicles; notch protein; novel; paracrine; public health relevance; regenerative; regenerative therapy; tool; transcriptome sequencing; translational study; treatment strategy

 DESCRIPTION (provided by applicant): This application responds to FOA PAR-13-114, "Improvement of Animal Models for Stem Cell-Based Regenerative Medicine", which encourages R01 applications aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease. The intent of that initiative is to facilitate the use of stem cell-based therapies for regenerative medicine, including demonstration of the functionality of specific stem cells or their derivatives and their effectiveness in improved anima models. The metabolic syndrome (MetS) is a constellation of cardiovascular risk factors, which induces kidney damage and raises the risk for chronic kidney disease, partly by rendering it vulnerable to ischemia. Indeed, MetS co- existing with renovascular disease (RVD) is linked to poorer outcomes after revascularization, possibly due to inflammation that characterizes MetS. However, tools to blunt its renal effects are yet to be identified, partly due to the lack of translational animal models of MetS and clinically applicable therapeutic tools. Adipose tissue-derived Mesenchymal stem cells (MSC) have potent paracrine anti-inflammatory properties, which recent studies have attributed to extracellular microvesicles (EV) that they release. Yet, the efficacy of EV delivery has not been tested in a large animal model. The goal of the current proposal is to develop and evaluate the capability of this novel platform to improve kidney viability in a novel swine model of MetS and RVD that we recently developed which closely mimics human pathophysiology and allows translational studies and interventions relevant to human clinical medicine. The hypothesis underlying this project is that similar to their parent MSC, MSC-derived EV is distinct and effective in decreasing damage in the kidney in MetS complicated by unilateral RVD. We will initially characterize the mRNA and micro-RNA expression pattern of EV in comparison to their parent MSC, and then assess their effects after intra-renal injection. To this end we will employ cutting-edge physiologic imaging techniques that we developed and refined, which are uniquely suited for studying the single kidney, including computed tomography and magnetic resonance imaging. Moreover, we will study the mechanism by which EVs mediate the benefits conferred by their parent MSC. Three specific aims will be pursued: Specific Aim 1 will test the hypothesis that MSC-derived EV show distinct patterns of mRNA and micro-RNA expression, which include enrichment with pro-angiogenic cargo. Specific Aim 2 will test the hypothesis that EV will attenuate injury of MetS-RVD kidneys. Specific Aim 3 will test the hypothesis that EVs mediate the paracrine angiogenic effects of their parent MSC via delta-like-4 signaling. The novel tools developed and employed in the proposed studies provide a unique opportunity to assess the feasibility of modifying renal outcomes in MetS/RVD using innovative and clinically applicable interventions and treatment platforms, which will likely contribute towards management strategies for patients with RVD & MetS.