Predicting Risk of Pneumonia in the General Population

预测普通人群的肺炎风险

基本信息

批准号：
8324619
负责人：
SACHIN YENDE
金额：
$ 11.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-02 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8324619
关键词：
Acute Advisory Committees Age Alleles Atherosclerosis Biological Assay Biological Markers Blood Tests Cause of Death Cell physiology Cells Clinical Clinical Data Clinical Trials Coagulation Process Cohort Studies Communities Comorbidity Complement Complex Critical Care Data Data Set Depressed mood Development Discipline Disease Early treatment Elderly Epidemiologist Funding Future General Population Genes Genetic Genetic Markers Genetic Variation Genotype Goals Health Hospitalization Immune Immune response Immune system Immunologic Markers Incidence Individual Infection Inflammation Inflammation Mediators Inflammatory Interdisciplinary Study Interleukin-6 Laboratories Lead Malignant Neoplasms Measures Mediator of activation protein Medicine Mentors Mentorship Modeling Molecular Patients Pattern Recognition Performance Plasma Plasminogen Activator Plasminogen Activator Inhibitor 1 Plasminogen Inactivators Pneumococcal vaccine Pneumonia Population Predisposition Prevention Prevention strategy Preventive Preventive Intervention Proteins Recording of previous events Research Research Personnel Research Proposals Resources Risk Risk Factors Role TNF gene Testing Training Translational Research United States United States National Institutes of Health Universities Validation Work base career case control checkup examination clinical practice clinically relevant cohort complex biological systems design experience follow-up functional genomics genetic variant high risk improved influenza virus vaccine insight interdisciplinary approach model development mortality multidisciplinary neutrophil novel prevent research study response success tool

项目摘要

DESCRIPTION (provided by applicant): My career goal is to successfully lead multidisciplinary translational research in critical care, focusing on the relationship between long-term health and episodes of acute illness, such as community-acquired pneumonia (CAP). I have the support of a leading Department of Critical Care Medicine at the University of Pittsburgh, uniquely suited for multidisciplinary research, and the commitment of an experienced and successful mentor, Dr. Derek Angus. Under his mentorship, I have assembled an advisory committee of a genetic epidemiologist, biostatistician, microbiologist, molecular biologist, and geriatrician. Training will complement my research proposal and include formal coursework and hands-on laboratory experience in each discipline. My research proposal focuses on susceptibility to CAP. My preliminary data have helped demonstrate that CAP occurs due to a complex interplay of clinical risk factors, genetic markers, circulating inflammatory molecules, and the efficiency of the immune system. In line with the NIH Roadmap initiative to prevent disease by improved understanding of such complex biological systems, I propose two parallel aims. First, I will develop and validate a multi-attribute pneumonia prediction tool using two large NIH-funded cohorts of healthy older adults comprising almost 10,000 patients with 10 years of follow-up and detailed clinical, genetic, and biomarker data. I hypothesize that a risk prediction model incorporating genetic and plasma biomarkers with detailed clinical information will outperform models based on simple clinical data alone. Rich as these datasets are, they lack markers of immune cell function, which could be very important in CAP susceptibility. Therefore, in my second aim, I will conduct preliminary experiments to explore the role of neutrophil function in CAP susceptibility. I will test the hypothesis that older adults with CAP have impaired neutrophil function. I will also conduct a functional genomics experiment to test the hypothesis that plasminogen activator inhibitor (PAI-1) genetic variants, associated with increased PAI-1 expression and increased risk of CAP in my preliminary work, influence neutrophil function. Aim 1 leverages resources of existing NIH cohorts to develop a clinically relevant risk prediction tool to target future prevention efforts. Aim 2 will generate preliminary data to incorporate novel functional assays in future prediction efforts and provide a functional basis for genetic markers that increase risk of CAP in gene-association studies. Together, these aims are also designed to provide valuable research practicums for my training as a translational researcher. PUBLIC HEALTH RELEVANCE Relevance for lay audience-Pneumonia is the most common infection and leading cause of death in the United States. A key problem is that we have only a crude notion of who will develop pneumonia to target preventive measures. The goal of this study is to develop a risk prediction tool based on a clinical exam and blood tests that could be done as part of a routine check-up to identify individuals at high risk for pneumonia.

描述（由申请人提供）：我的职业目标是成功领导重症监护的多学科翻译研究，重点是长期健康与急性疾病发作之间的关系，例如社区获得的肺炎（CAP）。我得到了匹兹堡大学重症监护医学领先的部门的支持，非常适合多学科研究，以及经验丰富且成功的导师Derek Angus博士的承诺。在他的指导下，我组建了一个遗传流行病学家，生物阶级主义者，微生物学家，分子生物学家和老年医生的咨询委员会。培训将补充我的研究建议，并在每个学科中包括正式的课程和动手实验室经验。我的研究建议着重于对CAP的易感性。我的初步数据有助于证明CAP是由于临床风险因素，遗传标记，循环炎症分子以及免疫系统效率的复杂相互作用而发生的。根据NIH路线图倡议，通过改善对这种复杂生物系统的了解来预防疾病，我提出了两个平行的目标。首先，我将使用两个大型NIH资助的健康老年人组成的大型肺炎预测工具并验证多属性肺炎预测工具，其中包括近10,000名有10年随访和详细临床，遗传和生物标志物数据的患者。我假设，仅基于简单的临床数据，将遗传和等离子体生物标志物与详细临床信息的风险预测模型与详细的临床信息相结合将胜过模型。像这些数据集一样丰富，它们缺乏免疫细胞功能的标记，这在帽易感性中可能非常重要。因此，在我的第二个目标中，我将进行初步实验，以探索中性粒细胞功能在CAP敏感性中的作用。我将检验以下假设，即具有CAP的老年人的中性粒细胞功能受损。我还将进行一个功能性基因组学实验，以检验以下假设：纤溶酶原激活剂抑制剂（PAI-1）遗传变异与我的初步工作中的PAI-1表达和CAP的增加有关，影响中性粒细胞功能。目标1利用现有的NIH队列的资源来开发一种与临床相关的风险预测工具，以针对未来的预防工作。 AIM 2将产生初步数据，以将新型功能测定纳入未来的预测工作中，并为在基因关联研究中增加CAP风险的遗传标记提供功能基础。这些目标还旨在为我作为翻译研究人员的培训提供宝贵的研究实践。公共卫生与外行观众 - 束缚的相关性是美国最常见的感染和主要死亡原因。一个关键问题是，我们只有一个粗略的概念，即谁会发展肺炎以靶向预防措施。这项研究的目的是根据临床检查和血液检查开发一种风险预测工具，可以作为常规检查的一部分进行，以识别患有高风险肺炎的人。