The Role of Integrins AlphaVBeta3 and AlphaVBeta5 in Acute Lung Injury

描述（由申请人提供）： 该提案详细介绍了一项为期5年的指导临床科学家发展奖（K 08）计划，旨在帮助乔治苏博士实现作为学术研究者的独立地位。苏博士对阐明急性肺损伤（All）发展的关键机制感兴趣。他最近发表的研究表明整联蛋白α ν β 3是肺血管通透性和肺内皮屏障功能的中心调节因子，两者都被认为是ALL整联蛋白α ν β 3的病理标志，与另一种整联蛋白α ν β 3共定位于局灶性粘连。两种整联蛋白识别相同的细胞外基质配体玻连蛋白。这两种整合素的聚集似乎是可诱导的水肿激动剂。尽管有这些相似之处，avps和avps的抑制对激动剂诱导的肺内皮通透性有相反的作用：avps的抑制是增强的，而avp 5的抑制是保护的。苏博士最近的研究表明，avps和avp 5差异调节肺内皮细胞中的细胞骨架排列; avps似乎是皮质肌动蛋白形成所必需的（屏障增强），而avp 5似乎是跨胞质应力纤维形成所必需的（与细胞旁通透性增加有关）。在该提案中，Su博士概述了一项计划，即绘制激动剂诱导的肺内皮通透性调节所需的avps和avps的关键结构域，定义avps和avps与先前确定的对皮质肌动蛋白和应力纤维形成重要的信号中间体的直接和功能性关联，并描述pS，P5，和双ps/p5亚基缺陷的小鼠急性淋巴细胞白血病通气诱导的肺损伤模型此外，为了帮助他的职业发展，苏博士组建了一个由备受尊敬的医生科学家组成的K 08顾问小组;开发了详细的教学培训课程，科学会议和研讨会的课程;并已获得UCSF医学系和肺部和重症监护医学部的全面承诺。充分利用所有必要的资源将使苏博士能够利用K 08的支持，作为肺科医学的医生科学家，建立一个富有成效和成功的学术生涯。相关性：仅在美国，ALI是一种与每年近75，000例死亡相关的综合征。目前尚无有效的药物治疗。苏博士以前的工作和初步数据表明，整合素avp和avp 5，细胞表面受体的整合素家族的特定成员，可能调节肺血管通透性，这是ALI的重要标志。这些拟议的研究可能支持这些整合素作为治疗靶点的有趣潜力，以调节肺血管通透性的疾病状态，如ALI。 (End摘要）

DESCRIPTION (provided by applicant): This proposal details a 5-year Mentored Clinical Scientist Development Award (K08) program designed to assist Dr. George Su in achieving independent status as an academic investigator. Dr. Su is interested in elucidating mechanisms critical to the development of acute lung injury (All). He has recently published work implicating integrin avps as a central regulator of lung vascular permeability and pulmonary endothelial barrier function-both considered pathologic hallmarks of ALL Integrin av(35 co-localizes with another integrin, avp3, at focal adhesions. Both integrins recognize the same extracellular matrix ligand vitronectin. Clustering of both integrins appears to be inducible by edemagenic agonists. Despite these similarities, inhibition of avps and avps have opposite effects on agonist-induced pulmonary endothelial permeability: inhibition of avps is enhancing, while inhibition of avp5 is protective. Dr. Su's recent studies suggest that avps and avp5 differentially regulate cytoskeletal arrangement in pulmonary endothelial cells; avps appears to be required for cortical actin formation (barrier-enhancing), while avp5 appears to be required for formation of transcytoplasmic stress fibers (associated with increased paracellular permeability). In this proposal, Dr. Su outlines a plan to map the critical domains of avps and avps that are required for regulation of agonist-induced pulmonary endothelial permeability, define direct and functional associations of avps and avps to signaling intermediates previously identified to be important for cortical actin and stress fiber formation, and to describe the effects of pS, P5, and double ps/p5 subunit deficiency in a mouse ventilation-induced lung injury model of ALL Furthermore, to assist with his career development, Dr. Su has assembled a K08 advisory panel of highly-regarded physician-scientists; has developed a detailed curriculum of didactic training courses, scientific conferences, and seminars; and has secured the full commitment of the UCSF Department of Medicine and the Division of Pulmonary and Critical Care Medicine. Full access to all necessary resources will allow Dr. Su to take advantage of K08 support towards building a productive and successful academic career as a physician-scientist in pulmonary medicine. Relevance: ALI is a syndrome associated with close to 75,000 deaths a year in the United States alone. Effective pharmacologic therapies are not currently available. Dr. Su's previous work and preliminary data suggest that integrins avps and avp5, specific members of the integrin family of cell surface receptors, may regulate pulmonary vascular permeability, an important hallmark of ALI. These proposed studies may support the intriguing potential of these integrins as therapeutic targets to modulate lung vascular permeability in disease states like ALI. (End of Abstract)