Variant Nucleotide Receptor Function in Airway Disorders

描述(由申请者提供)：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呼吸道疾病学术临床研究员的转变。长期的职业目标是成为一名独立资助的具有地方和国家领导潜力的临床调查员，专注于与呼吸道病原体流行病学相关的呼吸道疾病，并着眼于诊断和治疗这些感染的个性化药物。这项建议的目标是1)实际熟悉哮喘表型所需的技能，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。职业发展计划建议结合新的教学课程、研讨会和实践经验，利用威斯康星大学临床研究人员预备计划的需求评估、发展规划和评估方面的既定基础设施。指导委员会已经进行了重组，加入了新的智力影响，以塑造登林格博士的临床研究技能发展，并为每位导师制定了同步培训活动的详细计划。这将在威斯康星大学和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宿主特有的变异性，这些病原体有助于哮喘的急性和慢性病理生理学。一般说来，假设是核苷酸受体P2X7是一组对细胞内病原体的急性和慢性清除至关重要的先天免疫因子的一部分。赞助商和联合赞助商的拨款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活性的功能性筛查工具，并评估其作为急性和慢性哮喘风险因素的作用的手段。对原发肺泡巨噬细胞的P2X7反应的药物基因组分析也将在未来的临床试验中着眼于危险因素的修改。在通俗易懂的总结中，这项建议将促进对新的临床研究人员进行高水平的培训，他们对开发针对患者的新疗法感兴趣。哮喘的发病率和发病率不断上升，影响着7%的美国人口。

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.