Regulators of Endothelial Cell Apoptosis in LPS-Induced Acute Lung Injury

LPS 诱导的急性肺损伤中内皮细胞凋亡的调节因子

• 批准号: 7905035
• 负责人: RACHEL L DAMICO
• 金额: $ 13.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-12 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905035
• 关键词: Accounting; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Animal Disease Models; Animal Model; Apoptosis; Apoptosis Inhibitor; Apoptotic; Bacterial Toxins; Biology; Blood Vessels; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Complication; Cost of Illness; Critical Care; Crows; Data; Development; Disease; Disease model; Edema; Endothelial Cells; Environment; Event; Exposure to; Fellowship; Functional disorder; Goals; Homeostasis; Human; Hypoxemia; In Vitro; Infection; Inhibition of Apoptosis; Injury; Intervention; Lead; Length of Stay; Life; Lipopolysaccharides; Lung; Medical; Medicine; Mentors; Migration Inhibitory Factor; Modeling; Molecular; Molecular Biology; Mus; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Principal Investigator; Program Development; Protein Isoforms; Proteins; Public Health; Pulmonary Edema; Pulmonology; Regulation; Reporting; Research; Research Personnel; Resources; Role; Severities; Severity of illness; Techniques; Training; United States; Universities; Work; base; career; cell type; cytokine; improved; in vivo; in vivo Model; lung injury; lung vascular injury; mortality; mouse model; new therapeutic target; phenylpyruvate tautomerase; prevent; programs; response; skills; vascular inflammation

DESCRIPTION (provided by applicant): This proposal describes a 5 year mentored program for the development of an academic career in Pulmonary Medicine. The Principal Investigator has recently completed fellowship training in Pulmonary and Critical Care Medicine at Johns Hopkins University where she acquired extensive training in the use of cell and molecular techniques to investigate vascular pathobiology. She will extend her scientific skills through continuation of her work into animal models of disease. The co-sponsors of the program, Drs. Crow and Hassoun, are both experts in vascular biology, with Dr. Crow having expertise in the molecular biology of apoptosis and Dr. Hassoun in animal models of acute lung injury (ALI). Both provide the candidate with an excellent environment to accomplish the goals of this proposal. The research will focus on the molecular determinants of endothelial cell (EC) apoptosis in ALI and the physiological consequences of this mode of vascular injury. ALI has a substantial impact on public health accounting for 75,000 U.S. deaths per year. Mortality rates are 30-60% and treatment remains supportive only. A greater understanding of the molecular and cellular determinants of the disease is necessary to identify new therapeutic targets. The Pi's work demonstrates that ALI induced by intratracheal exposure to the bacterial toxin lipopolysaccharide (LPS) is associated with early EC apoptosis in the lung and vascular leak. Further, her work demonstrates that macrophage migration inhibitory factor (MIF) is a determinant of EC responses to LPS. MIF antagonizes LPS-induced apoptosis, in part, through its role in regulating the inhibitor of apoptosis, FLICE-like Inhibitory Protein (FLIPs). This proposal will characterize the physiologic effects of EC apoptosis on vascular dysfunction in a direct lung injury model of ALI and the contributions of MIF and FLIPs in the regulation of this mechanism of vascular injury. The initial aim focuses on the contribution of EC apoptosis to ALI in a direct lung injury model of disease. The second aim defines the impact of MIF deficiency on vascular dysfunction in vivo and in culture. The final aim defines the mechanism by which MIF regulates FLIPs and its effects on LPS-induced apoptosis. These studies will improve our understanding of the factors regulating apoptosis in ALI, information that could lead to new therapies.

描述（由申请人提供）：此提案描述了一个为期5年的肺医学学术生涯发展指导计划。首席研究员最近在约翰霍普金斯大学完成了肺部和重症监护医学的奖学金培训，在那里她获得了使用细胞和分子技术研究血管病理生物学的广泛培训。她将通过继续研究动物疾病模型来扩展她的科学技能。该项目的共同发起人，dr。Crow和Hassoun都是血管生物学的专家，Crow博士在细胞凋亡的分子生物学方面有专长，Hassoun博士在急性肺损伤（ALI）的动物模型方面有专长。两者都为候选人提供了一个很好的环境来完成这个提案的目标。研究将集中在ALI中内皮细胞（EC）凋亡的分子决定因素和这种血管损伤模式的生理后果。急性呼吸道感染对公共卫生有重大影响，美国每年有7.5万人死亡。死亡率为30-60%，治疗仍然只是支持性的。更好地了解疾病的分子和细胞决定因素对于确定新的治疗靶点是必要的。Pi的研究表明，气管内暴露于细菌毒素脂多糖（LPS）诱导的ALI与肺和血管渗漏的早期EC凋亡有关。此外，她的工作表明，巨噬细胞迁移抑制因子（MIF）是EC对LPS反应的决定因素。MIF拮抗lps诱导的细胞凋亡，部分是通过调节细胞凋亡抑制剂flic样抑制蛋白（FLIPs）的作用。本研究将描述在急性肺损伤模型中EC凋亡对血管功能障碍的生理作用，以及MIF和FLIPs在血管损伤机制中的调节作用。最初的目的是关注在疾病的直接肺损伤模型中，EC细胞凋亡对ALI的贡献。第二个目标是确定体内和培养中MIF缺乏对血管功能障碍的影响。最终目的是确定MIF调节FLIPs的机制及其对lps诱导的细胞凋亡的影响。这些研究将提高我们对ALI中调节细胞凋亡因素的理解，这些信息可能会导致新的治疗方法。