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

描述(申请人提供)：这是为加州大学旧金山分校的住院医生Kirsten Kangelaris博士申请K23奖项。Kangelaris博士在急性肺损伤(ALI)的临床研究中以患者为导向，致力于了解影响易感性的生物和遗传因素，使自己成为一名年轻的研究员。 非裔美国人急性肺损伤的转归和预后。K23奖项将为Kangelaris博士提供必要的支持，以实现以下目标：(1)成为急性肺损伤方面以患者为导向的临床和翻译研究专家；(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机制；(3)在临床研究中应用先进的生物统计技术，包括高级回归和生物信息学；以及(4)发展独立的临床研究事业。为了实现这些目标，Kangelaris博士组建了一个多学科团队，成员包括一位主要导师Michael Matthay博士和两位共同导师：Elad Ziv博士和Bradley Aouizerat博士。Matthay博士在翻译和以发病机制为导向的ALI研究以及向独立研究人员指导初级教员方面拥有丰富的经验，Elad Ziv博士是混合人群遗传图谱的专家，Bradley Aouizerat博士是基因组学和分子流行病学的领导者。此外，Kangelaris博士还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发生率和死亡率最高。Kangelaris博士的研究计划建立在她的初步数据基础上，以检验非裔美国人ALI发病机制中趋化因子依赖的途径。她将研究Duffy抗原/趋化因子受体基因(Darc-46C/C，rs2814778)功能多态在非洲人后裔中的作用，在她的前期工作中，这种多态与更糟糕的ALI结局有关，可能是通过循环中白细胞介素8(IL-8)的增加。Kangelaris博士将测试这种所谓的“Dufy Null”基因与急性肺损伤易感性的关联程度(Aim 1)，确定Duffy Null基因是否与急性肺损伤患者之间Duffy结合的趋化因子水平(例如IL-8)和损伤生物标志物的差异有关(Aim 2)，并使用全血基因表达来确定非裔美国患者急性肺损伤发病机制中与趋化因子相关的途径(Aim 3)。这项研究计划利用了加州大学旧金山分校的Carolyn Calfee博士的肾和肺损伤早期评估(EARLI)队列和Vanderbilt大学的Lorraine Ware博士的急性肺损伤诊断(有效)队列的生物标记物验证的现有基础设施。这项研究将为R01水平的应用奠定基础，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人患者的急性肺损伤易感性和预后之间的关系。

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.