Mentoring Research in Precision Medicine for Lung Disease

项目摘要 通过将对设计的坚定理解和严格的人体研究与不断增长的 作为分子生物学家和遗传学家的工具包，现代以患者为导向的医生科学家有潜力 为了克服常见和病态呼吸道疾病靶向治疗发展的古老障碍， 疾病因此，本次K24指导补助金更新申请的第一个目标是继续保护我的 指导年轻的研究科学家在哮喘和COPD患者导向的转化研究的时间。 这项工作是第一个资助期所开展工作的自然延伸，并建立在我的成功的基础上 我的研究项目的资助将进一步增加。这些指导工作 通过提供空间来启动和扩展“肺精确”，得到了UCSF的大力支持 医学核心实验室”，我指导，并提供可扩展的空间和资源和一个共同的领域 为教学和非正式的研究互动的学员在病人为导向的研究（POR）。K24项目 我已经大大保护了我的时间，并提供了资源（一些由分区资源匹配），以确保 这一奋进的成功。在我最近受到启发要追求的一个新方向上，第二个目标 这次K24更新的目的是支持我在研究种族差异方面的指导工作， 治疗阻塞性肺病。这个新的研究领域直接来自我和两个学员的新数据， 是由我指导的纵向队列研究SPIROMICS产生的。这些数据突出了系统性偏差， 从研究和临床护理中使用的种族调整的肺功能测试方程。在其 结构，这个K24更新申请提出了三个科学目标和第四个组织目标， 描述了我扩展核心培训实验室和研讨会系列的方法， 利用更大的新空间，这是赋予我的肺科和部门 医学在UCSF的基础上，这些计划的成功，以日期。目标1将检验气道 上皮内质网应激确定了一个共同的途径，与T2和干扰素驱动的 炎症，并与哮喘中疾病严重程度和加重风险增加相关， 慢性阻塞性肺病目的2将检验这一假设，即维持纤毛和解毒途径在气道 吸烟者的上皮与吸烟者的临床恢复力有关。目标3将检验我们的假设， 目前肺功能正常化的实践从根本上是有偏见的， 方程式可以更好地衡量我们多元化社会中的健康和疾病。目标4将检验以下假设： 我所开发的“肺部精准医学核心实验室”将加强多学科培训 在一系列具有不同科学背景的受训者中，使他们能够很好地扩展自己的能力。 超越现有的核心培训，同时专注于人类研究和POR。

PROJECT SUMMARY By combining a firm understanding of the design and conduct of rigorous human studies with the growing toolkit of the molecular biologist and geneticist, modern patient-oriented physician-scientists have the potential to overcome age-old barriers to the development of targeted therapies in common and morbid respiratory diseases. Accordingly, the first goal of this K24 Mentoring grant renewal application is to continue to protect my time for mentoring of young research scientists in patient oriented translational research in asthma and COPD. This work is a natural extension of work undertaken in the first funding period and builds on the success of my mentees and in further increases in NIH grant support of my research programs. These mentoring efforts have been strongly supported by UCSF through the provision of space to start and expand a “Pulmonary Precision Medicine Core Laboratory” that I direct and which provides scalable space and resources and a common area for didactics and informal research interactions for mentees in patient oriented research (POR). This K24 grant has significantly protected my time and provided resources (some matched by Divisional resources) to ensure the success of this endeavor. In a new direction that I have recently been inspired to pursue, the second goal of this K24 renewal is to support my mentoring efforts in the study of racial disparities in how we assess and treat obstructive lung disease. This new research area flows directly from new data that I and two mentees generated in SPIROMICS, the longitudinal cohort that I direct. These data highlight systematic bias that results from race-adjusted pulmonary function testing equations that are used in research and clinical care. In its structure, this K24 renewal application proposes three scientific aims and a fourth organizational aim which describes my approach to expanding the core training laboratory and seminar series that I have developed by leveraging larger new space that is being conferred to me by the Pulmonary Division and Department of Medicine at UCSF based on the success of these programs to date. Aim 1 will test the hypothesis that airway epithelial endoplasmic reticulum stress identifies a common pathway related to both T2 and interferon-driven inflammation and which is associated with increased disease severity and exacerbation risk in asthma and COPD. Aim 2 will test the hypothesis that maintenance of cilia and detoxifying pathways in the airway epithelium of smokers is associated with clinical resilience in smokers. Aim 3 will test the hypothesis that our current practices for lung function normalization are fundamentally biased and that race-agnostic PFT equations better measure health and disease in our diverse society. Aim 4 will test the hypothesis that the “Pulmonary Precision Medicine Core Laboratory” that I have developed will enhance multidisciplinary training across a range of trainees with diverse scientific backgrounds and enable them to expand their capabilities well beyond their existing core training, while focusing on human studies and POR.