Variant Nucleotide Receptor Function in Airway Disorders

描述（由申请人提供）：本提案的目标是对Loren Denlinger博士进行高级培训，以完成他从基础科学家到气道疾病学术临床研究者的转变。长期职业目标是成为一名独立资助的临床研究者，具有地方和国家领导潜力，专注于流行病学与呼吸道病原体相关的气道疾病，并着眼于诊断和治疗这些感染的个性化医学。本提案的目标是：1）实际熟悉哮喘表型分析所需的技能，2）利用流行病学方法将基础科学发现转化为临床研究假设，3）发展项目管理，领导和商业技能。职业发展计划提出了新的教学课程，研讨会和实习经验的组合，利用需求评估，发展规划和威斯康星州临床研究者预备计划的大学评估的既定基础设施。指导委员会已经重组，包括新的智力影响，以塑造Denlinger博士的临床研究技能发展，并与每个导师同步培训活动的详细计划。这将在威斯康星州大学和NHLBI哮喘临床研究中心提供的丰富环境中进行。科学的重点是对细胞内呼吸道病原体的免疫反应中的宿主特异性变异性，这些病原体有助于哮喘的急性和慢性病理生理学。一般来说，假设是核苷酸受体P2X7是一组先天性免疫因子的一部分，对细胞内病原体的急性和慢性清除很重要。申办者和联合申办者的资助和临床试验的辅助方案提供了在流行病学数据库中测试P2X7活性的功能筛查工具并评估其作为急性和慢性哮喘风险因素的作用的方法。在未来的临床试验中，还将对原代肺泡巨噬细胞的P2X7反应进行药物基因组学分析，并着眼于风险因素的改变。通俗地说，该提案将促进对新的临床研究者进行高水平的培训，这些研究者有兴趣开发针对哮喘的新的患者特异性疗法，这种疾病影响7%的美国人口，患病率和发病率不断增加。

DESCRIPTION (provided by applicant): The goal of this proposal is the advanced training of Dr. Loren Denlinger to complete his transition from a basic scientist to an academic clinical investigator in airway diseases. The long range Career Goal is to become an independently funded clinical investigator with local and national leadership potential, focusing on airway disorders linked epidemiologically to respiratory pathogens, and with a view towards personalized- medicine for the diagnosis and treatment of these infections. The Objectives for this proposal are to 1) become practically familiar with the skills needed for asthma phenotyping, 2) utilize epidemiological methods to translate basic science findings to clinical research hypotheses, and 3) develop project management, leadership, and business skills. The Career Development plan proposes a combination of new didactic courses, workshops, and practicum experiences, taking advantage of the established infrastructure in needs assessment, development planning and evaluation of the University of Wisconsin Clinical Investigator Preparatory Program. The Mentoring Committee has been restructured to include new intellectual influences to shape Dr. Denlinger's clinical research skills development, and a detailed plan with each mentor synchronizing training activities. This will take place within the rich environment provided by the University of Wisconsin and the NHLBI Asthma Clinical Research Center. The scientific focus is on the host-specific variability in the immune response to intracellular respiratory pathogens that contribute to the acute and chronic pathophysiology of asthma. Generally stated, the hypothesis is that the nucleotide receptor P2X7 is part of a set of innate immune factors important to the acute and chronic clearance of intracellular pathogens. Ancillary protocols to the Sponsor and Co-Sponsor's grant and clinical trial provide the means to test a functional screening tool for P2X7 activity within epidemiological databases and assess its role as a risk factor in both acute and chronic asthma. Pharmacogenomic analysis of the P2X7 responses of primary alveolar macrophages will also be performed with an eye toward risk factor modification in future clinical trials. In lay-language summary, this proposal will promote high-level training of a new clinical investigator interested in developing new patient-specific therapies for asthma, a condition affecting 7% of the U.S. population with an increasing prevalance and morbidity.