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的右心（RV）功能结合在一起，RV衰竭（RVF）是特发性肺纤维化患者（IPF）的直接原因。然而，对于从代偿性RV肥大到RV失败的响应PAH的过渡过程中的分子机制知之甚少。特别是，目前尚不清楚RV失败是由于后负荷作用而出现的，还是肺脉管系统的疾病是否需要RVF进展。为了解决这些局限性并回应NHLBI RFA HL-12-021，我们组建了一个多学科的研究人员团队，具有IPF生物学，肺血管生物学，心力衰竭和骨髓生物学专业知识的专业知识明尼苏达大学将对患有严重PAH的进行性IPF的患者进行I期MSC的I期临床试验，并且无法选择肺移植。 MSC表现出我们用来改善纤维化肺损伤的抗炎能力。 MSC能够将其线粒体转移到其他细胞上，并挤出外泌体，内吞作用的囊泡，以将RNA作为细胞之间遗传交换的机制传递。由MSC分泌的外泌体减少了小鼠的心肌缺血/再灌注损伤。但是，在RV/PA耦合受损的背景下，从未以集成方式研究MSC。我们提出了一个总体假设，即MSC或其产品（外部或TSG-6）保留RV/PA偶联，并通过对肺肺疾病的RV肌细胞的线粒体功能对肺循环的肺循环和独立改善来防止RV失败。方法：我们将利用一种多学科的方法来实现研究的两个主要目标：1）在肺损伤（bleomycin诱导的）综合模型中验证使用MSC或其产品在预防和治疗纤维化肺病和RV失败中，并在肺部循环中独立于肺部循环（PABIS）和2 emand; Pabing; Pabing; Pabing; Pabing; Pa branging; Pabing; Pabing; Pa branging; Pabing; Pabing; Pa branging; Pabing; Pa branging; Pa branging; Pa branging; 2）人性间质性肺部疾病的线粒体功能障碍，预期这些疾病中MSC的概念转化安全性和机理研究证明。我们提出以下具体目的：1）确定MSC在防止RV转变为PAH动物模型中从补偿到失败的失败的功效； 2）确定由于进行性IPF而导致的PAH患者MSC的安全性。这些目标的结论将增强我们当前对PAH动物模型和受试者受到渐进式ILD的受试者中RV遗传学的了解，这是我们首次能够确定行动机制以及MSC在IPF相关PAH患者中的安全性和安全性和潜在功效。