Chemokine-related acute lung injury pathogenesis in African-American patients

描述（由申请人提供）：这是一份K23奖的申请，申请人是弗朗西斯科加州大学的一名住院医生Kirsten Kangelaris博士。Kangelaris博士是一名年轻的急性肺损伤（ALI）患者导向临床研究的研究者，专注于了解影响易感性的生物和遗传因素 非裔美国人急性肺损伤的发病率和预后。该K23奖将为Kangelaris博士提供必要的支持，以实现以下目标：（1）成为急性肺损伤领域以患者为导向的专业临床和转化研究人员;（2）结合遗传学，蛋白质标记物和功能基因组学等创新方法，阐明急性肺损伤的遗传和生物学机制;（3）在临床研究中实施先进的生物统计技术，包括先进的回归和生物信息学;（4）发展独立的临床研究生涯。为了实现这些目标，Kangelaris博士组建了一个多学科团队，由一位主要导师Michael Matthay博士和两位共同导师组成：Elad Ziv博士，混合人群遗传图谱专家，以及布拉德利Aouizerat博士，基因组学和分子流行病学的领导者。Michael Matthay博士在转化型、以发病机制为导向的ALI研究方面拥有丰富的经验，并在指导初级教师和独立研究人员方面拥有丰富的经验。此外，Kangelaris博士将受益于几位科学顾问的专业知识。急性肺损伤（ALI）是住院患者急性呼吸衰竭的常见原因，非洲裔美国人的ALI发病率和死亡率最高。Kangelaris博士的研究计划建立在她的初步数据的基础上，以研究非洲裔美国人ALI发病机制的趋化因子依赖途径。她将研究Duffy抗原/趋化因子基因受体（Darc-46 C/C，rs 2814778）的功能多态性的作用，该基因在非洲裔个体中普遍存在，在她的初步工作中，可能通过循环白细胞介素（IL）-8的增加与更严重的ALI结果相关。Kangelaris博士将测试这种所谓的“Duffy无效”基因型与急性肺损伤易感性相关的程度（目的1），确定Duffy无效基因型是否与Duffy结合趋化因子水平的差异相关（例如，IL-8）和急性肺损伤患者中损伤的生物标志物（目的2），并使用全血基因表达来鉴定非洲裔美国患者中急性肺损伤发病机制的趋化因子相关途径（目的3）。本研究计划利用了UCSF的Carolyn Calfee博士的肾和肺损伤早期评估（EARLI）队列和范德比尔特大学的Lorraine Ware博士的急性肺损伤诊断（VALID）队列生物标志物验证的现有基础设施。这项研究将成为R 01级应用的基础，以研究趋化因子相关的基因组和蛋白质标记物与非洲裔美国患者急性肺损伤易感性和结局之间的关系。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Kirsten Kangelaris, a hospitalist at the University of California, San Francisco. Dr. Kangelaris is establishing herself as a young investigator in patient-oriented clinical research in acute lung injury (ALI), with a focus on understanding biologic and genetic factors that impact susceptibility to and prognosis in acute lung injury among African-American patients. This K23 award will provide Dr. Kangelaris with the support necessary to accomplish the following goals: (1) to become an expert patient-oriented clinical and translational researcher in acute lung injury; (2) to elucidate genetic and biologic mechanisms of acute lung injury combining innovative approaches including genetics, protein markers and functional genomics; (3) to implement advanced biostatistical techniques in clinical studies, including advanced regression and bioinformatics; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Kangelaris has assembled a multidisciplinary team comprised of a primary mentor, Dr. Michael Matthay, who has extensive experience in translational, pathogenesis-oriented ALI research, and in mentoring junior faculty to independent investigators, and two co-mentors: Dr. Elad Ziv, an expert in genetic mapping in admixed populations, and Dr. Bradley Aouizerat, a leader in genomics and molecular epidemiology. Additionally, Dr. Kangelaris will benefit from the expertise of several scientific advisors. Acute lung injury (ALI) is a common cause of acute respiratory failure in hospitalized patients, and African Americans suffer the highest ALI incidence and mortality rates. Dr. Kangelaris' research plan builds on her preliminary data to examine chemokine-dependent pathways of ALI pathogenesis in African-American patients. She will study the role of a functional polymorphism in the Duffy antigen/receptor for chemokines gene (Darc -46C/C, rs2814778), prevalent in individuals of African descent, that has been associated with worse ALI outcomes in her preliminary work, possibly via an increase in circulating interleukin (IL)-8. Dr. Kangelaris will test the extent to which this so-called "Dufy null" genotype is associated with susceptibility to acute lung injury (Aim 1), determine whether the Duffy null genotype is associated with differences in Duffy- binding chemokine levels (e.g., IL-8) and biomarkers of injury among patients with acute lung injury (Aim 2), and to use whole blood gene expression to identify chemokine-related pathways of acute lung injury pathogenesis in African-American patients (Aim 3). This research plan makes use of the existing infrastructure of Dr. Carolyn Calfee's Early Assessment of Renal and Lung Injury (EARLI) cohort at UCSF and Dr. Lorraine Ware's Validation of biomarkers in Acute Lung Injury Diagnosis (VALID) cohort at Vanderbilt University. This research will form the basis for an R01-level application to study the association between chemokine-related genomic and protein markers and acute lung injury susceptibility and outcomes in African-American patients.