The Role of Integrins AlphaVBeta3 and AlphaVBeta5 in Acute Lung Injury

描述(由申请人提供)： 这项建议详细介绍了一个为期5年的临床科学家发展指导奖(K08)项目，旨在帮助乔治·苏博士获得独立的学术研究人员地位。苏博士对阐明急性肺损伤(ALL)发生的关键机制很感兴趣。他最近发表的研究表明，整合素AVPs是肺血管通透性和肺内皮屏障功能的中央调节因子，这两种功能都被认为是所有整合素av的病理特征(35与另一种整合素avp3共同定位于局灶性粘连。这两种整合素识别相同的细胞外基质配体Vitronectin。这两种整合素的聚集似乎可以被促通水的激动剂诱导。尽管有这些相似之处，但AVP和AVP的抑制对激动剂诱导的肺内皮细胞通透性的影响是相反的：AVP的抑制作用是增强的，而AVP的抑制是保护性的。Su博士最近的研究表明，Avp和avp5分别调节肺内皮细胞的细胞骨架排列；Avp似乎是皮质肌动蛋白形成(屏障增强)所必需的，而avp5似乎是形成跨细胞质应激纤维所必需的(与细胞旁通透性增加有关)。在这项建议中，苏博士概述了一项计划，以绘制AVP和AVP调节激动剂诱导的肺内皮细胞通透性所需的关键区域，定义AVP和AVP与先前被认为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关联，并描述PS、P5和双PS/P5亚单位缺陷在小鼠呼吸机致ALL肺损伤模型中的影响。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内科科学家组成的K08顾问小组；制定了详细的教学培训课程、科学会议和研讨会；并得到了加州大学旧金山分校医学部和肺部和重症监护医学部的全力支持。充分利用所有必要的资源将使苏博士能够利用K08的支持，建立一个富有成效和成功的学术生涯，成为一名肺部内科的内科科学家。相关性：ALI是一种综合征，仅在美国每年就有近7.5万人死亡。目前还没有有效的药物治疗方法。Su博士以前的工作和初步数据表明，整合素Avps和avp5是细胞表面受体整合素家族的特定成员，可能调节肺血管通透性，这是ALI的一个重要标志。这些拟议的研究可能支持这些整合素作为治疗靶点在ALI等疾病状态下调节肺血管通透性的有趣潜力。 (摘要结束)

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)