SELPLG as a candidate gene in Acute Respiratory Distress Syndrome

SELPLG 作为急性呼吸窘迫综合征的候选基因

基本信息

批准号：
10383770
负责人：
Christian Bime
金额：
$ 17.27万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-09 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383770
关键词：
Acute Acute Respiratory Distress Syndrome Address Affect African ancestry Antibodies Arizona Bioinformatics Biology Blood Platelets Blood Vessels Candidate Disease Gene Caring Clinical Code Conduct Clinical Trials Critical Care Critical Illness DNA DNA Repository Data Development E-Selectin Endothelium Exhibits Extravasation Funding Gene Expression Gene Frequency Genes Genetic Genetic Determinism Genotype Individual Inflammation Inflammatory K-Series Research Career Programs L-Selectin Laboratories Lead Leukocytes Ligands Luciferases Lung Lung infections MYLK gene Medicine Mentors Mentorship Minor Modeling Not Hispanic or Latino P-Selectin P-selectin ligand protein Pathway interactions Patients Persons Phenotype Physicians Pre-Clinical Model Predisposition Preventive Proteins Race Regulation Reporter Research Research Personnel Risk Risk Factors Role SELE gene Sampling Scientist Selectins Sepsis Severities Single Nucleotide Polymorphism Site Stimulus Susceptibility Gene Systems Biology Testing Therapeutic Training United States National Institutes of Health Universities Variant Ventilator-induced lung injury antagonist attenuation base biobank career cohort design experience functional genomics genetic variant genome wide association study health disparity in vitro activity in vivo individualized medicine insight lung injury mortality mouse model non-genetic novel personalized medicine pre-clinical professor programs promoter racial disparity recruit skills translational therapeutics

项目摘要

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.

摘要/摘要：这项指导的临床科学家研究职业发展奖（K08）的申请涉及急性呼吸窘迫综合征（ARDS）的风险和严重程度的种族差异的重要问题，严重的急性重症疾病，死亡率高（约30％），每年影响多达200,000名美国患者。与非 - 非洲血统的受试者相比西班牙裔白人。越来越多地赞赏遗传因素参与确定 ARDS的易感性，可能导致观察到的健康差异。另外，对 ARDS敏感性的遗传决定因素将加快新颖的个性化预防和治疗方法来护理。该K08应用程序的PI是医学助理教授亚利桑那大学渴望从事与转化有关的职业破译遗传和非遗传因素是重症监护和重症监护术中观察到的健康差异的基础探索ARDS中的个性化疗法。 PI接受了肺和重症监护的临床培训医学以及临床试验设计和行为的培训和经验。他现在建议将其研究的范围和范围扩展到ARDS的转化系统生物学计划和重症监护。在乔·GN Garcia医学博士的指导下，该领域是世界知名的医师科学家 ARDS，遗传学和健康差异，PI产生了重要的初步数据，暗示了Selectin P配体（SELPLG）基因及其编码的蛋白P-选择蛋白糖蛋白配体1（PSGL1）作为新颖非洲血统个体中ARDS的敏感性目标。拟议的研究将采用重点以及综合系统生物学方法来检验SELPLG和PSGL1是新颖的假设 ARDS靶标具有赋予敏感性的遗传变异。特定的目标＃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基因启动子活动SA＃2将表征SELPLG编码SNP对PSGL1活动的影响 ARDS的临床前模型。最后，SA＃3将评估Selectin途径基因SNP与利用序列质量群体基因分型平台的风险和死亡率来自DNA 存储库存储在我们的亚利桑那大学生物库中。因此，高级K08辅助培训遗传学，功能基因组学，生物信息学分析和肺损伤生物学将具有较高的转化治疗意义，并将增强PI成功过渡到独立的可能性研究职业的重点是转化障碍和健康差异。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting SELPLG/P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter.

DOI：
10.1002/pul2.12206
发表时间：
2023-01
期刊：
PULMONARY CIRCULATION
影响因子：
2.6
作者：
Sun, Xiaoguang;Sammani, Saad;Hufford, Matthew;Sun, Belinda L.;Kempf, Carrie L.;Camp, Sara M.;Garcia, Joe G. N.;Bime, Christian
通讯作者：
Bime, Christian

The ARREST Pneumonia Clinical Trial. Rationale and Design.

ARREST 肺炎临床试验。

DOI：
10.1513/annalsats.202009-1115sd
发表时间：
2021
期刊：
Annals of the American Thoracic Society
影响因子：
8.3
作者：
Levitt,JosephE;Festic,Emir;Desai,Manisha;Hedlin,Haley;Mahaffey,KennethW;Rogers,AngelaJ;Gajic,Ognjen;Matthay,MichaelA;ARRESTPneumoniaClinicalTrialInvestigators
通讯作者：
ARRESTPneumoniaClinicalTrialInvestigators

High-Flow Oxygen Therapy Concepts: Time to Standardize Nomenclature and Avoid Confusion.

高流量氧疗概念：是时候标准化命名并避免混淆了。