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HUMAN LUNG NEUTRAL METALLOENDOPEPTIDASE

人肺中性金属内肽酶

基本信息

批准号：
3082727
负责人：
BRUCE C MARSHALL
金额：
$ 8.26万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-09-01 至 1994-08-31
项目状态：
已结题

项目摘要

The applicant proposes to learn and apply the tools of cell biology and molecular biology to a research area relevant to human lung disease. A number of regulatory peptides with potent physiologic pro-inflammatory, and growth promoting effects have been localized to the lung. A neutral metalloendopeptidase (NEP) appears to play a key role in degrading many of these peptides. The modulation of NEP will thus likely impact on the extent of the peptides' effects. NEP has recently been localized to the lung and evidence suggests that it is relevant to reactive airways disease. The long term objective is to understand the role and regulation of NEP in normal and diseased human airways. The specific aims of this proposal are to: 1) Fully characterize the purified human lung NEP from a structural, functional, and immunological standpoint. 2) Clone the gene from human cDNA and genomic libraries. The deduced amino acid sequence will likely provide additional information on the structure and function of the enzyme. This work will also provide the tools necessary to examine regulation of NEP at the transcriptional level. 3) Comprehensively assess modulation of epithelial cell NEP from the transcriptional to post-translational level. This work will consist of three major thrusts. The first will be a systematic screening of potential modulating factors in epithelial cell cultures. The second will be an examination of the effects of specific modulating factors on synthesis and degradation of NEP utilizing metabolic labelling and immunoprecipitation. The final thrust will be an incorporation of the DNA probe into the studies for an assessment of transcriptional regulation. The environment at the University of Utah is ideal for developing the investigative career of the applicant. Within the Pulmonary Division, or closely aligned, are a capable group of investigators with a wide range of interests from basic biochemistry, immunology, and molecular biology to physics and clinical physiology. Pulmonary research conferences, seminars, and journal clubs foster open communication in the Division. The sponsors of this proposal, Dr. John Hoidal and Dr. Ray White, are highly productive investigators with an excellent track record in developing young people. The University of Utah is particularly strong in the area of molecular biology and this proposal taps that potential. Through the application of the techniques of molecular biology to this proposal, the interaction with other basic science faculty and trainees with similar interests, and graduate course work, the applicant will gain a solid foundation in molecular biology.

申请人建议学习和应用细胞生物学的工具和分子生物学到与人类肺部疾病相关的研究领域。许多具有强效生理促炎作用的调节肽，生长促进作用已定位于肺部。中立的金属内肽酶 (NEP) 似乎在降解许多这些肽。因此，NEP 的调整可能会影响程度肽的作用。 NEP 最近已定位于肺部有证据表明它与反应性气道疾病有关。长期目标是了解 NEP 在正常和患病的人类呼吸道。该提案的具体目标是 1) 从结构、功能和免疫学的观点。 2) 从人类cDNA中克隆基因和基因组文库。推导的氨基酸序列可能会提供有关酶结构和功能的其他信息。这工作还将提供必要的工具来审查 NEP 的监管转录水平。 3）综合评估调制上皮细胞NEP从转录到翻译后水平。这项工作将包括三个主要重点。第一个将是系统筛选上皮细胞中潜在的调节因子文化。第二步是检查具体措施的效果利用代谢调节 NEP 合成和降解的因素标记和免疫沉淀。最后的推动力将是将 DNA 探针纳入研究中以评估转录调控。犹他大学的环境非常适合发展申请人的调查生涯。在肺科内，或密切配合，是一个有能力的研究人员小组，具有广泛的基础生物化学、免疫学和分子生物学的兴趣物理学和临床生理学。肺研究会议、研讨会、和期刊俱乐部促进该部门的开放式沟通。赞助商 John Hoidal 博士和 Ray White 博士对这项提案的提出非常有成效调查员在培养年轻人方面有着出色的记录。犹他大学在分子领域尤其强大生物学和这项提案挖掘了这种潜力。通过分子生物学技术的应用提案、与其他基础科学教师和学员的互动具有相似的兴趣和研究生课程，申请人将获得扎实的分子生物学基础。