RV/PA Recoupling by Bone Marrow Derived Mesenchymal Stem Cells

骨髓间充质干细胞的 RV/PA 重新偶联

基本信息

批准号：
9105405
负责人：
Luis Alberto Ortiz
金额：
$ 57.92万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105405
关键词：
Address Aging Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Anti-inflammatory Biology Bleomycin Blood Vessels Bone Marrow Cardiovascular Diseases Cause of Death Cells Collaborations Complex Coupled Coupling Development Disease Endocytic Vesicle Eukaryotic Cell Exhibits Failure Financial compensation Gene Expression Generations Genes Genetic Goals Hamman-Rich syndrome Health Heart Heart failure Human Immune Inflammation Mediators Injury Interstitial Lung Diseases Knowledge Lung Lung Transplantation Lung diseases Malignant Neoplasms Mediating Mesenchymal Stem Cells MicroRNAs Minnesota Mitochondria Modeling Molecular Molecular Profiling Mus Muscle Cells Myocardial Ischemia National Heart, Lung, and Blood Institute Organ Organelles Parkinson Disease Patients Phase I Clinical Trials Prevention Production Pulmonary Circulation Regulation Reperfusion Injury Research Research Personnel Right Ventricular Function Right Ventricular Hypertrophy Role Safety Therapeutic Time Transfer RNA United States National Institutes of Health Universities Vascular Diseases Ventricular Ventricular Remodeling Vesicle coping effective therapy exosome experience human data human study interdisciplinary approach knowledge base lung injury macrophage mitochondrial dysfunction multidisciplinary origen outcome forecast pressure prevent programs pulmonary arterial hypertension response stem cell biology

项目摘要

DESCRIPTION (provided by applicant): The pulmonary circulation is coupled with the right ventricular (RV) function in health and disease and RV failure (RVF) is the immediate cause of death in patients with idiopathic pulmonary fibrosis (IPF). However, little is known about the molecular mechanisms operative during the transition from compensatory RV hypertrophy to RV failure in response to PAH. In particular, it is not clear whether RV failure develops exclusively as a consequence of afterload effects or whether disease of the lung vasculature is required for RVF progression. To address these limitations and in response to the NHLBI RFA HL-12-021 we assembled a multidisciplinary team of researchers with expertise in the biology of IPF, lung vascular biology, heart failure, and bone marrow derived mesenchymal stem cell (MSC) biology at the University of Pittsburgh and established a collaboration with the NIH HLBI sponsored Production Assistance for Cellular therapies program at the University of Minnesota to conduct a phase I clinical trial of MSCs for patients afflicted with progressive IPF who experience severe PAH and for whom lung transplantation in not an option. MSCs exhibit anti-inflammatory capacity that we have used to ameliorate fibrotic lung injury. MSCs are capable of transferring their mitochondria to other cells and to extrude exosomes, vesicles of endocytic origin, to transfer RNAs as a mechanism of genetic exchange between cells. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury in mice. However, MSCs have never been studied in an integrated manner in the context of impaired RV/PA coupling. We propose the Overall Hypothesis that MSCs or their products (exosomes or TSG-6) preserve RV/PA coupling and prevents RV failure via pleotropic actions on both the pulmonary circulation and an independent improvement in the mitochondrial function of the RV myocyte in the setting of fibrotic lung disease. Approach: We will utilize a multidisciplinary approach to accomplish two main goals of the study: 1) To validate the use of MSCs or their products in the prevention and treatment of fibrotic lung disease and RV failure in established integrated models of lung injury (bleomycin-induced) and RV failure independent of injury in the pulmonary circulation (PA banding; PAB) and 2) characterize the role of endogenous TSG-6 and RV mitochondrial dysfunction in human interstitial lung disease in anticipation of a proof of concept translational safety and mechanistic human study of MSC in these diseases. We propose the following Specific Aims: 1) To determine the efficacy of MSCs in preventing the RV transition from compensation to failure in animal models of PAH; 2) To determine the safety of MSCs in patients with PAH as a result of progressive IPF. Conclusion of these Aims will enhance our current knowledge of the genetics of the failing RV in animal models of PAH and in subjects afflicted by progressive ILD and for the first time we will be able to determine the mechanisms of action and the safety and potential efficacy of MSC in patients with IPF-associated PAH.

描述（由申请人提供）：肺循环与健康和疾病中的右心室（RV）功能相关，右心室衰竭（RVF）是特发性肺纤维化（IPF）患者死亡的直接原因。然而，对于 PAH 反应从代偿性右心室肥大到右心室衰竭转变过程中的分子机制知之甚少。特别是，尚不清楚 RV 衰竭是否完全是后负荷效应的结果，或者肺血管系统疾病是否是 RVF 进展所必需的。为了解决这些限制并响应 NHLBI RFA HL-12-021，我们组建了一个多学科研究团队，他们在 IPF 生物学、肺血管生物学、心力衰竭和骨髓源性间充质干细胞 (MSC) 生物学方面具有专业知识，匹兹堡大学并与 NIH HLBI 赞助的明尼苏达大学细胞疗法生产援助计划建立合作，为患者进行 MSC 的 I 期临床试验患有进行性 IPF、患有严重 PAH 且无法选择肺移植的患者。间充质干细胞表现出抗炎能力，我们已将其用于改善纤维化肺损伤。 MSC 能够将线粒体转移到其他细胞，并挤出外泌体（内吞来源的囊泡），转移 RNA 作为细胞间遗传交换的机制。 MSC 分泌的外泌体可减轻小鼠心肌缺血/再灌注损伤。然而，从未在 RV/PA 耦合受损的情况下以综合方式研究 MSC。我们提出总体假设，即 MSC 或其产品（外泌体或 TSG-6）保留 RV/PA 偶联，并通过对肺循环的多效性作用和 RV 肌细胞线粒体功能的独立改善来防止 RV 衰竭。纤维化肺病。方法：我们将利用多学科方法来实现研究的两个主要目标：1）验证 MSC 或其产品在已建立的肺损伤综合模型（博莱霉素-诱导）和与肺循环损伤无关的 RV 衰竭（PA 带；PAB）和 2）表征了内源性 TSG-6 和 RV 线粒体功能障碍在人类间质性肺疾病中的作用，以预测MSC 在这些疾病中的概念转化安全性和机制人体研究的证明。我们提出以下具体目标： 1) 确定 MSC 在预防 PAH 动物模型中 RV 从代偿向衰竭转变中的功效； 2) 确定间充质干细胞在进展性IPF导致的PAH患者中的安全性。这些目标的结论将增强我们目前对 PAH 动物模型和患有进行性 ILD 的受试者中失败的 RV 遗传学的了解，并且我们将首次能够确定作用机制以及安全性和潜在功效。 IPF 相关 PAH 患者的 MSC。