UPREGULATION OF 5-LIPOXYGENASE IN ALVEOLAR MACROPHAGES

申请人：申请人是内科讲师， 证明了在临床和 基础科学研究 这些临床研究和基础科学 调查结果已在高质量的同行评审期刊上发表。 他致力于基础肺生物学的研究事业， 80%的精力用于研究活动，并寻求临床研究者 发展奖，以支持他的发展成为一个独立的 调查员 环境：肺和重症监护医学部， 密歇根大学医学院提供了一个特殊的 科学环境。 的非凡支持和专业知识， 申请人的担保人（马克·彼得斯-戈尔登博士），丰富的经验， 我的培训委员会成员（Galen Toews博士、Joseph Fantone博士 和大卫金斯伯格），并咨询了一位基础科学专家， 5-脂氧合酶（5-LO）激活区，（吉利埃文斯博士），将有助于 确保提案和调查的成功执行 申请人在临床研究者任期内的成长 发展奖。 研究：5-LO代谢产物在肺内发挥重要作用 炎症 鉴于肺泡巨噬细胞（AM）表现出异常的 高能力的白三烯（LT）的合成，申请人已经 研究了AM中5-LO的调节作用。 本提案的目标是 阐明AM中5-LO代谢的分子机制， 上调。 基于培养的AM表现出时间- 5-LO能力的依赖性下降，一般假设是， 肺泡环境中的成分上调5-LO代谢， 单核细胞在肺内分化成AM。 具体假设 5-LO和FLAP蛋白的数量和功能的改变 解释AM中5-LO的上调。 最初，大鼠AM将是 在培养中研究，LT合成随时间下降， 与5-LO代谢调节机制的变化相关。 的 具体目的是确定AM中5-LO容量的降低， 从肺泡腔中取出，与：1）定性或 5-LO和/或FLAP蛋白质的定量改变;和2）功能性 5-LO和FLAP活性的改变。 具体目标3）是确定 如果肺泡衬里液是导致5-LO容量增加的原因， AM通过其防止培养的细胞中5-LO代谢降低的能力， 随着时间的推移。 如果5-LO代谢可以上调，具体目标4）是 确定肺泡衬液是否能够直接上调LT 单核细胞合成和改变5-LO激活机制， 类似于AM。 这些研究应能增进我们的基本了解 巨噬细胞5-LO调节的一般和特别是在肺。 最终，他们可能会导致新的方法来调节 炎症和免疫性肺病。

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.