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

• 批准号: 8907806
• 负责人: Luis Alberto Ortiz
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907806
• 关键词: Address; Aging; Alzheimer' 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; 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

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，RV衰竭（RVF）是特发性肺纤维化（IPF）患者死亡的直接原因。然而，对PAH从代偿性RV肥大向RV衰竭转变过程中的分子机制知之甚少。特别是，目前尚不清楚右心室衰竭是否完全是后负荷效应的结果，或者肺血管疾病是否是RVF进展所必需的。为了解决这些局限性并响应NHLBI RFA HL-12-021，我们组建了一个多学科研究团队，该团队具有IPF生物学、肺血管生物学、心力衰竭、和骨髓间充质干细胞（MSC）生物学，并与明尼苏达大学NIH HLBI赞助的细胞疗法生产援助计划建立了合作，对患有进展性IPF的重度PAH患者进行I期MSC临床试验，对于这些患者，肺移植不是一种选择。 MSC表现出抗炎能力，我们已经用来改善纤维化肺损伤。MSC能够将其线粒体转移到其他细胞，并挤出外泌体，内吞来源的囊泡，以转移RNA作为细胞之间遗传交换的机制。MSC分泌的Exosome减轻小鼠心肌缺血/再灌注损伤然而，骨髓间充质干细胞从来没有被研究在一个完整的方式在受损的RV/PA耦合的上下文中。我们提出了总体假设，即MSC或其产物（外泌体或TSG-6）通过对肺循环的多效性作用和在纤维化肺病背景下RV肌细胞线粒体功能的独立改善来保持RV/PA偶联并预防RV衰竭。方法：我们将利用多学科的方法来完成本研究的两个主要目标：1）在已建立的肺损伤综合模型中验证MSC或其产品在预防和治疗纤维化肺疾病和RV衰竭中的用途（博来霉素诱导）和RV衰竭与肺循环损伤无关（PA显带; PAB）和2）表征内源性TSG-6和RV线粒体功能障碍在人类间质性肺病中的作用，以预期MSC在这些疾病中的概念转化安全性和机制人类研究的证明。我们提出了以下具体目的：1）确定MSC在PAH动物模型中预防RV从代偿转变为衰竭的疗效; 2）确定MSC在因进行性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RV的遗传学的了解，并且我们将首次能够确定MSC在IPF相关PAH患者中的作用机制以及安全性和潜在疗效。