SELPLG as a candidate gene in Acute Respiratory Distress Syndrome

摘要/摘要： 这份临床科学家导师研究职业发展奖(K08)的申请书针对 急性呼吸窘迫综合征(ARDS)风险和严重程度的种族差异这一重要问题 严重的急性危重疾病死亡率高(约30%)，每年影响多达200,000名美国患者。 与非非洲裔受试者相比，非洲裔受试者表现出更高的ARDS风险和更高的死亡率 西班牙裔白人。人们越来越认识到，遗传因素参与了决定 易患急性呼吸窘迫综合征，可能导致观察到的健康差距。此外，对 ARDS易感性的遗传决定因素将加速新型个性化预防和治疗的发展 ARDS护理的治疗方法。这份K08申请书的私人助理是一名医学助理教授， 亚利桑那大学，他立志从事与以下相关的翻译ARDS研究 破译在重症监护和护理中观察到的健康差异的遗传和非遗传因素 探索ARDS的个性化治疗。专科医生接受过肺部和重症护理方面的临床培训。 医学，以及在设计和进行临床试验方面的培训和经验。他现在提议 将他的研究范围扩展到ARDS的翻译系统生物学计划和 重症监护室。在乔·加西亚医学博士的指导下，他是世界著名的内科医生兼科学家 ARDS、遗传学和健康差异，PI已经产生了与选择相关的重要初步数据 P-选择素糖蛋白配体1(P-选择素糖蛋白配体1)基因及其编码蛋白 非洲人后裔的急性呼吸窘迫综合征的易感目标。拟议的研究将采用集中的 和综合系统生物学方法来检验SELPLG和PSGL1是新的假设 ARDS靶点具有可赋予ARDS易感性的遗传变异。具体目标#1(SA#1)将描述 ARDS刺激和精选SELPLG启动子SNPs对SELPLG表达的调控 SELPLG基因启动子活性SA#2将表征编码SELPLG的SNPs对PSGL1活性的影响 ARDS的临床前模型。最后，SA#3将评估选择素途径基因SNPs与 利用Sequenom Massarray基因分型平台对不同井进行ARDS风险和死亡率的研究 来自DNA的ARDS患者DNA样本(2,000)和健康对照(种族匹配)的表型队列 存储在我们亚利桑那大学生物库中的储存库。因此，K08-支持高级培训 遗传学、功能基因组学、生物信息学分析和肺损伤生物学将有很高的翻译水平 治疗意义，并将增加PI成功过渡到独立的 研究生涯专注于转化性ARDS和健康差异。

SUMMARY/ABSTRACT: This application for a Mentored Clinical Scientist Research Career Development Award (K08) addresses the important issue of racial disparities in both risk and severity for acute respiratory distress syndrome (ARDS), a severe acute critical illness with a high mortality rate (~30%) affecting up to 200,000 US patients each year. Subjects of African descent exhibit increased ARDS risk and higher ARDS mortality compared with non- Hispanic whites. It has been increasingly appreciated that genetic factors participate in determining predisposition to ARDS and may contribute to observed health disparities. Additionally, an understanding of genetic determinants of ARDS susceptibility will hasten the development of novel personalized preventive and therapeutic approaches to ARDS care. The PI for this K08 application is an Assistant Professor of Medicine at the University of Arizona who aspires to a career focused on translational ARDS research related to deciphering the genetic and non-genetic factors that underlie the observed health disparities in critical care and to exploring personalized therapies in ARDS. The PI has clinical training in pulmonary and critical care medicine, as well as training and experience in the design and conduct of clinical trials. He now proposes to extend the reach and scope of his research towards a translational systems biology program in ARDS and critical care. Under the mentorship of Joe GN Garcia MD, a world-renowned physician-scientist in the field of ARDS, genetics, and health disparities, the PI has generated important preliminary data implicating the selectin P ligand (SELPLG) gene and its encoded protein, P-selectin glycoprotein ligand 1 (PSGL1) as novel susceptibility targets for ARDS in individuals of African descent. The proposed research will employ a focused and comprehensive systems biology approach to test the hypothesis that SELPLG and PSGL1 are novel ARDS targets with genetic variants that confer ARDS susceptibility. Specific Aim #1 (SA #1) will characterize the regulation of SELPLG expression by ARDS stimuli and carefully-selected SELPLG promoter SNPs on SELPLG gene promoter activity SA #2 will characterize effects of SELPLG coding SNPs on PSGL1 activity in preclinical models of ARDS. Finally, SA #3 will assess the association of selectin pathway gene SNPs with ARDS risk and mortality utilizing the Sequenom MassARRAY genotyping platform on a diverse well- phenotyped cohort of ARDS patient DNA samples (>2,000) and healthy controls (race-matched) from the DNA repository stored within our University of Arizona biobank. Thus, the K08-suported training in advanced genetics, functional genomics, bioinformatic analysis, and lung injury biology, will have high translational therapeutic implications and will enhance the likelihood that the PI will successfully transition to an independent research career focused on translational ARDS and health disparities.