Mesenchymal Stem Cells for Treatment of Acute Lung Injury

间充质干细胞治疗急性肺损伤

基本信息

批准号：
7667927
负责人：
Jae Woo Lee
金额：
$ 12.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-04 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667927
关键词：
Acute Lung Injury Adult Respiratory Distress Syndrome Advisory Committees Air Allogenic Alveolar Anti-Inflammatory Agents Anti-inflammatory Area California Cardiovascular system Carrier Proteins Cell Therapy Critical Care Edema Endotoxins Environmental air flow Epithelial Functional disorder Genes Genetic Transcription Goals Grant Growth Factor Hepatocyte Growth Factor Human In Vitro Individual Inflammatory Inflammatory Response Injury Innovative Therapy Interleukin-10 Lead Liquid substance Lung Membrane Protein Traffic Mesenchymal Mesenchymal Stem Cells Methods Modeling Molecular Biology Multiple Abnormalities Mus Nature Pathogenesis Patients Permeability Plasmids Preparation Property Proteins Pulmonary Edema Recombinant Proteins Research Research Institute Research Personnel Resolution Role San Francisco Severities Small Interfering RNA Sodium Stem cells Stimulus Testing Therapeutic Therapeutic Effect Transfection Translations Type II Epithelial Receptor Cell Universities Whole Blood anakinra base clinically relevant cytokine improved in vitro Model in vivo injured innovation insight keratinocyte lung injury monolayer mortality overexpression paracrine programs public health relevance response skills

项目摘要

DESCRIPTION (provided by applicant): This is a K08 application from Jae-Woo Lee, MD, an anesthesiologist at the University of California, San Francisco, who is establishing himself as an investigator in the use of cell-based therapy with mesenchymal stem cells (MSC) for treatment of acute lung injury. This application will provide Dr. Lee with the support necessary to accomplish the following goals: (1) develop two innovative and synergistic human acute lung injury models; (2) obtain expertise with molecular biology methods to study the mechanism underlying the therapeutic effect of MSC; and (3) develop cell-based therapy with MSC transfected with plasmids overexpressing key soluble factors. To achieve these goals, Dr. Lee has assembled a Scientific Advisory Committee chaired by Dr. Michael A. Matthay, a renowned intensivist and expert in acute lung injury within the Cardiovascular Research Institute at UCSF. By the end of the grant, Dr. Lee will become an independent investigator focused on translational critical care research in the area of acute lung injury. In this application, Dr. Lee will test the hypothesis that allogeneic human mesenchymal stem cells will restore alveolar fluid clearance and maintain lung endothelial permeability by modulating the proinflammatory response and by up-regulating the release of protective growth factors and anti-inflammatory cytokines in two innovative models of human acute lung injury. MSC, due to its pluripotent nature and its ability to secrete multiple paracrine factors such as growth factors (KGF, HGF) and anti-inflammatory cytokines (IL-10, IL-1ra) can treat multiple abnormalities simultaneously. In Aim 1, he will determine the mechanistic effects of human MSC on alveolar epithelial fluid transport in an in vitro model of human alveolar epithelial type II cells grown in Transwell plates with an air-liquid interface that are injured by cytomix, a mixture of the most biologically active cytokines found in ALI pulmonary edema fluid (IL-1f3, TNFa and IFNv). In Aim 2, he will test the therapeutic effect of intrapulmonary instillation of human MSC on alveolar epithelial fluid clearance and lung endothelial permeability after the establishment of endotoxin injury in an ex vivo perfused human lung preparation. In Aim 3, he will determine if transfection of allogeneic human MSC with plasmids over-expressing key soluble factors will lead to further protection in terms of alveolar fluid clearance and lung endothelial and epithelial permeability to protein in both human lung injury models. The support from this K08 grant will provide Dr. Lee with the necessary skills to become a successful independent investigator. Public Health Relevance: Despite extensive research into the pathophysiology, mortality from acute respiratory distress syndrome remains at 40%. Current treatment options remain primarily supportive with lung protective ventilation and fluid conservative strategy. Innovative therapies are needed.

描述（由申请人提供）：这是加利福尼亚大学旧金山分校的麻醉师Jae-woo Lee的K08申请，他正在将自己确立为使用中充质干细胞（MSC）使用基于细胞的治疗的研究者，以治疗急性肺损伤。该应用将为Lee博士提供实现以下目标所需的支持：（1）开发两个创新且协同的人类急性肺损伤模型；（2）获得分子生物学方法的专业知识，以研究MSC治疗作用的基础机制；（3）用过表达关键可溶性因子转染的MSC开发基于细胞的治疗。为了实现这些目标，李博士组建了一个科学咨询委员会，该委员会由UCSF心血管研究所内著名的强化主义者兼急性肺损伤专家迈克尔·A·马特（Michael A. Matthay）主持。在赠款结束时，李博士将成为一名专注于急性肺损伤领域转化重症监护研究的独立研究者。在此应用中，Lee博士将检验以下假设：同种异性人间充质干细胞将通过调节促炎反应并上调保护性生长因子和两种创新的人类急性肠道受损模型中的抗炎细胞因子来恢复肺泡液清除并保持肺内皮渗透性。 MSC由于其多能性质及其分泌多种旁分泌因子（例如生长因子（KGF，HGF）和抗炎细胞因子（IL-10，IL-1RA））的能力，可以同时治疗多种异常。在AIM 1中，他将确定人类MSC对肺泡上皮流体转运的机理影响，在人肺泡上皮II型II型细胞的体外模型中，在Transwell平板中生长的，其空中液体界面受细胞溶液损伤，该模型受到细胞体的损伤，这是Ali Plimonary Edema falemy and flyemial and and-il-1fa）的混合物，该混合物的混合物（IL-1FA）在Ali肺动脉肿瘤中发现了最活跃的细胞因子。在AIM 2中，他将测试人类MSC内肺内滴注对肺泡上皮流体清除率和肺内皮渗透性后的治疗作用，该肺内毒素损伤是在体内灌注的人类肺中造成的。在AIM 3中，他将确定用过表达的关键可溶性因子转染同种异体人类MSC是否会导致在两个人类肺损伤模型中对肺泡液清除率以及对蛋白质的肺内皮和上皮渗透性的进一步保护。这项K08赠款的支持将为Lee博士提供成为成功的独立调查员的必要技能。公共卫生相关性：尽管对病理生理学的广泛研究，急性呼吸窘迫综合征的死亡率仍为40％。当前的治疗方案主要通过肺部保护性通风和流体保守策略提供支持。需要创新的疗法。