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

描述(由申请者提供)：这份建议书描述了一个5年制的肺部医学学术生涯发展指导计划。这位首席研究员最近在约翰·霍普金斯大学完成了肺部和重症护理医学的研究员培训，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。她将通过继续她的工作来扩展她的科学技能到疾病的动物模型。该项目的共同发起人Crow博士和Hassoun博士都是血管生物学方面的专家，其中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)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实现本提案的目标。研究将集中在ALI中内皮细胞(EC)凋亡的分子决定因素以及这种血管损伤模式的生理学后果。ALI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%，治疗仍然是支持性的。为了确定新的治疗靶点，有必要更好地了解疾病的分子和细胞决定因素。PI的工作表明，由于气管内暴露于细菌毒素脂多糖(LPS)而导致的ALI与早期肺内皮细胞凋亡和血管渗漏有关。此外，她的工作表明，巨噬细胞移动抑制因子(MIF)是EC对内毒素反应的决定因素。MIF拮抗内毒素诱导的细胞凋亡，部分是通过调节细胞凋亡抑制因子--FLICE样抑制蛋白(FLOPS)的作用实现的。本研究将探讨血管内皮细胞凋亡在ALI直接肺损伤模型血管功能障碍中的生理学作用，以及MIF和FLOPS在血管损伤机制中的作用。最初的目的是在疾病的直接肺损伤模型中内皮细胞凋亡在ALI中的作用。第二个目的是确定MIF缺乏对体内和培养的血管功能障碍的影响。最终目的是明确MIF调控FLOPS的机制及其对内毒素诱导的细胞凋亡的影响。这些研究将提高我们对ALI中调节细胞凋亡的因素的理解，这些信息可能会导致新的治疗方法。

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.