SELPLG as a candidate gene in Acute Respiratory Distress Syndrome

总结/摘要： 本申请为指导临床科学家研究职业发展奖（K 08）解决了 急性呼吸窘迫综合征（ARDS）风险和严重程度的种族差异是一个重要问题， 严重急性危重病，死亡率高（约30%），每年影响多达20万美国患者。 与非非洲裔受试者相比，非洲裔受试者显示出增加的ARDS风险和更高的ARDS死亡率。 西班牙裔白人越来越多的人认识到，遗传因素参与决定 易患ARDS，并可能导致观察到的健康差异。此外，了解 ARDS易感性的遗传决定因素将加速新的个性化预防和 ARDS治疗方法。本K 08申请的PI是医学助理教授， 亚利桑那大学谁渴望职业生涯专注于翻译ARDS研究有关 破译遗传和非遗传因素的基础上观察到的健康差异，在重症监护， 探索成人呼吸窘迫综合征的个性化治疗。PI接受过肺部和重症监护方面的临床培训 医学，以及临床试验设计和实施方面的培训和经验。他现在提议， 将他的研究范围和范围扩展到呼吸窘迫综合症的转化系统生物学项目， 重症监护在Joe GN Garcia医学博士的指导下，他是世界知名的医学科学家， 急性呼吸窘迫综合征，遗传学和健康差异，PI已经产生了重要的初步数据， 一种新的P配体（SELPLG）基因及其编码蛋白，P-选择素糖蛋白配体1（PSGL 1 非洲裔个体的ARDS易感性目标。该研究将采用一个集中的 和全面的系统生物学方法来检验SELPLG和PSGL 1是新的假设 ARDS靶向具有赋予ARDS易感性的遗传变异。具体目标#1（SA #1）将表征 通过ARDS刺激和精心选择的SELPLG启动子SNP对SELPLG表达的调节， SELPLG基因启动子活性SA#2将表征SELPLG编码SNP对PSGL 1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SNP与 利用Sequenom MassARRAY基因分型平台在不同井- 表型队列的ARDS患者DNA样品（> 2，000）和健康对照（种族匹配）， 储存在我们亚利桑那大学的生物库中。因此，K 08支持的高级培训 基因组学、功能基因组学、生物信息学分析和肺损伤生物学，将有很高的翻译价值。 治疗意义，并将提高PI成功过渡到独立治疗的可能性。 研究生涯主要集中在转化性呼吸窘迫综合症和健康差异上。

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.