Mesenchymal Stem Cells for Treatment of Acute Lung Injury

间充质干细胞治疗急性肺损伤

• 批准号: 8115099
• 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
• 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/8115099
• 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; Stromal Cells; 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

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(申请人提供)：这是加州大学旧金山分校的麻醉学家Lee Jae-woo医学博士提交的一份K08申请书，他正在利用间充质干细胞(MSC)进行基于细胞的治疗来治疗急性肺损伤，成为一名研究人员。这一应用将为Lee博士提供必要的支持，以实现以下目标：(1)开发两种创新和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治疗效果的潜在机制；以及(3)开发MSC基于细胞的治疗方法，其中MSC高表达关键可溶性因子。为了实现这些目标，李博士组建了一个科学咨询委员会，由加州大学旧金山分校心血管研究所内著名的急性肺损伤强化专家迈克尔·A·马泰博士担任主席。到拨款结束时，李博士将成为一名独立研究员，专注于急性肺损伤领域的转化性危重护理研究。 在这项应用中，Lee博士将验证这样一个假设，即同种异体人类间充质干细胞将通过调节促炎反应和上调保护性生长因子和抗炎细胞因子的释放，在两种人类急性肺损伤创新模型中恢复肺泡液清除并维持肺内皮细胞通透性。骨髓间充质干细胞具有多能性，能分泌多种旁分泌因子，如生长因子(KGF、HGF)和抗炎细胞因子(IL-10、IL-1ra)，可同时治疗多种异常情况。在目标1中，他将在一个体外模型中确定人类MSC对肺泡上皮液转运的影响，该模型的人肺泡上皮II型细胞生长在具有气液界面的Transwell平板中，受到细胞因子(一种在ALI肺水肿液中发现的最具生物活性的细胞因子(IL-1f3、TNFa和IFNv)的混合物)的损伤。 在目标2中，他将在体外人肺灌流制备的内毒素损伤建立后，测试肺内注入人MSC对肺泡上皮液清除和肺内皮细胞通透性的治疗效果。在目标3中，他将确定在两种人类肺损伤模型中，将高表达关键可溶性因子的质粒导入同种异体人MSC是否会在肺泡液清除和肺内皮细胞对蛋白质的通透性方面产生进一步的保护作用。K08基金的资助将为李博士提供成为一名成功的独立调查员所需的技能。 公共卫生相关性：尽管对病理生理学进行了广泛的研究，但急性呼吸窘迫综合征的死亡率仍保持在40%。目前的治疗方案仍然主要支持肺保护性通气和液体保守策略。需要创新的治疗方法。