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.

 描述（由申请人提供）：本申请响应 FOA PAR-13-114，“基于干细胞的再生医学的动物模型的改进”，它鼓励 R01 应用旨在表征动物干细胞并改进现有的并创建新的人类疾病动物模型。该计划的目的是促进基于干细胞的疗法在再生医学中的应用，包括展示特定干细胞或其衍生物的功能及其在改进动物模型中的有效性。代谢综合征（MetS）是一系列心血管危险因素，它会导致肾脏损伤并增加患慢性肾脏病的风险，部分原因是使其容易发生缺血。事实上，MetS 与肾血管疾病 (RVD) 共存与血运重建后较差的结果有关，这可能是由于 MetS 特有的炎症所致。然而，减弱其肾脏影响的工具尚未确定，部分原因是缺乏 MetS 的转化动物模型和临床适用的治疗工具。脂肪组织来源的间充质干细胞 (MSC) 具有有效的旁分泌抗炎特性，最近的研究将其归因于它们释放的细胞外微泡 (EV)。然而，EV 输送的功效尚未在大型动物模型中进行测试。当前提案的目标是开发和评估这个新平台的能力，以提高我们最近开发的 MetS 和 RVD 新型猪模型的肾脏活力，该模型密切模仿人类病理生理学，并允许与人类临床医学相关的转化研究和干预。该项目的假设是，与母体 MSC 类似，MSC 衍生的 EV 在减少 MetS 并发单侧 RVD 的肾脏损伤方面具有独特且有效的作用。我们将首先表征 EV 与其亲代 MSC 相比的 mRNA 和 micro-RNA 表达模式，然后评估肾内注射后的效果。为此，我们将采用我们开发和完善的尖端生理成像技术，这些技术特别适合研究单个肾脏，包括计算机断层扫描和磁共振成像。此外，我们将研究 EV 介导其母体 MSC 赋予的益处的机制。将追求三个具体目标： 具体目标 1 将测试以下假设：MSC 衍生的 EV 显示出不同的 mRNA 和 micro-RNA 表达模式，其中包括富集促血管生成货物。具体目标 2 将检验 EV 将减轻 MetS-RVD 肾脏损伤的假设。具体目标 3 将测试 EV 通过 delta-like-4 信号传导介导其亲本 MSC 的旁分泌血管生成作用的假设。拟议研究中开发和使用的新工具提供了一个独特的机会，可以评估使用创新且临床适用的干预措施和治疗平台改变 MetS/RVD 肾脏结局的可行性，这可能有助于制定 RVD 和 MetS 患者的管理策略。