UPREGULATION OF 5-LIPOXYGENASE IN ALVEOLAR MACROPHAGES

申请人：申请人是一名内科讲师， 在临床和临床方面表现出原创性研究的能力 基础科学研究。这些临床研究和基础科学 调查已在高质量的同行评议期刊上发表。 他致力于基础肺部生物学的研究事业，并致力于 他80%的精力致力于研究活动，并寻求临床研究人员 发展奖，支持他发展成为一个独立的 调查员。 环境：肺和危重病医学部 密歇根大学医学院提供了一种特殊的 科学环境。非同寻常的支持和专业知识 申请人的赞助人(Marc Peters-Golden博士)，拥有丰富的 我培训委员会的成员(Galen Toews博士、Joseph Fantone博士 和David Ginsburg)，并咨询了基础科学家专家 5-脂氧合酶(5-LO)激活区域(Jilly Evans博士)将有所帮助 确保成功执行建议书和调查 申请人在临床调查员任期内的成长情况 发展奖。 研究：5-LO代谢物在肺部疾病中发挥重要作用 发炎。鉴于肺泡巨噬细胞(AM)表现出不寻常的 白三烯(LT)合成能力高，申请人有 研究AM中5-LO的调节本提案的目标是 阐明AM中5-LO代谢的分子机制 调高了。基于培养的AM表现出一段时间- 依赖于5-LO能力的下降，一般假设是 肺泡环境中的成分上调5-LO代谢为 单核细胞在肺内分化为AM。具体的假设 5-LO和翻盖蛋白的数量和功能的变化 AM中5-LO上调的原因最初，RAT AM将是 在培养中的研究和LT合成的时间依赖性下降 与5-LO代谢调节机制的变化有关。这个 具体目标是确定AM中5-LO容量是否降低， 从牙槽间隙中取出，与：1)质的或 5-LO和/或翻盖蛋白的数量变化；2)功能 5-LO和皮片活动的改变。具体目标3)是确定 如果肺泡衬里液体是增加的5-LO容量的原因 AM，通过其阻止培养的细胞5-LO代谢减少的能力 随着时间的推移。如果5-LO代谢可以上调，具体目标就是 确定肺泡衬里液体是否能直接上调LT 单核细胞合成及改变5-LO活化机制 与AM相似这些研究应该提高我们的基本认识 巨噬细胞5-LO调节的一般，特别是在肺。 最终，它们可能会导致新的方法来调制 炎症性和免疫性肺部疾病。

Applicant: The applicant is a Lecturer in Internal Medicine who has demonstrated an aptitude for original investigation both in clinical and basic science research. These clinical studies and basic science investigations have been published in high quality peer review journals. He is committed to a research career in basic pulmonary biology and devotes 80% of his effort to research activity and seeks the Clinical Investigator Development Award to support his development into an independent investigator. Environment: The Division of Pulmonary and Critical Care Medicine and Medical School at the University of Michigan provide an exceptional scientific environment. The extraordinary support and expertise of the applicant's sponsor (Dr. Marc Peters-Golden), the extensive experience of the members of my training committee (Drs. Galen Toews, Dr. Joseph Fantone and David Ginsburg), and consultation with a basic scientist expert in the area of 5-lipoxygenase (5-LO) activation, (Dr. Jilly Evans), will help ensure the successful execution of the proposal and the investigative growth of the applicant during the term of the Clinical Investigator Development Award. Research: 5-LO metabolites play an important role in pulmonary inflammation. Given that alveolar macrophages (AM) exhibit an unusually high capacity for the synthesis of leukotrienes (LT), the applicant has studied the regulation of 5-LO in AM. The goal of the present proposal is to elucidate the molecular mechanisms by which 5-LO metabolism in AM is upregulated. Based on the finding that cultured AM exhibit a time- dependent decline in 5-LO capacity, the general hypothesis is that the constituents in the alveolar environment upregulate 5-LO metabolism as monocytes differentiate into AM within the lung. The specific hypothesis is that alterations in the amount and function of 5-LO and FLAP proteins account for the upregulation of 5-LO in AM. Initially, rat AM will be studied in culture and the time-dependent decline in LT synthesis correlated with changes in mechanisms regulating 5-LO metabolism. The specific aims are to determine whether decreased 5-LO capacity in AM, removed from the alveolar space, is associated with: 1) qualitative or quantitative alterations in 5-LO and or FLAP proteins; and 2) functional alterations in 5-LO and FLAP activities. Specific aim 3) is to determine if alveolar lining fluid is responsible for the increased 5-LO capacity of AM, by its ability to prevent the reduction of 5-LO metabolism in cultured AM over time. If 5-LO metabolism can be upregulated, specific aim 4) is to determine if alveolar lining fluid is capable of directly upregulating LT synthesis in monocytes and altering the mechanisms of 5-LO activation to resemble those of AM. These studies should enhance our basic understanding of macrophage 5-LO regulation in general and specifically in the lung. Eventually they may lead to new approaches for the modulation of inflammatory and immunologic pulmonary disease.