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：
8127994
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8127994
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领域的多学科转化研究，重点关注长期健康与社区获得性肺炎（CAP）等急性疾病发作之间的关系。我得到了匹兹堡大学重症监护医学系的支持，该系非常适合多学科研究，并且得到了经验丰富且成功的导师德里克·安格斯博士的承诺。在他的指导下，我组建了一个由遗传流行病学家、生物统计学家、微生物学家、分子生物学家和老年病学家组成的咨询委员会。培训将补充我的研究计划，包括每个学科的正式课程和实验室实践经验。我的研究计划重点关注 CAP 的易感性。我的初步数据有助于证明 CAP 的发生是由于临床危险因素、遗传标记、循环炎症分子和免疫系统效率之间复杂的相互作用所致。根据 NIH 路线图倡议，通过增进对此类复杂生物系统的了解来预防疾病，我提出了两个并行目标。首先，我将使用 NIH 资助的两个大型健康老年人队列（包括近 10,000 名患者）开发并验证多属性肺炎预测工具，并进行 10 年的随访和详细的临床、遗传和生物标志物数据。我假设，将遗传和血浆生物标志物与详细临床信息相结合的风险预测模型将优于仅基于简单临床数据的模型。尽管这些数据集很丰富，但它们缺乏免疫细胞功能的标记，而这对于 CAP 易感性可能非常重要。因此，在我的第二个目标中，我将进行初步实验来探讨中性粒细胞功能在CAP易感性中的作用。我将检验患有 CAP 的老年人中性粒细胞功能受损的假设。我还将进行功能基因组学实验，以检验以下假设：纤溶酶原激活剂抑制剂 (PAI-1) 遗传变异与我的前期工作中 PAI-1 表达增加和 CAP 风险增加相关，影响中性粒细胞功能。目标 1 利用现有 NIH 队列的资源开发临床相关的风险预测工具，以针对未来的预防工作。目标 2 将生成初步数据，将新的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。总之，这些目标还旨在为我作为转化研究员的培训提供有价值的研究实践。公共卫生相关性与非专业观众的相关性——肺炎是美国最常见的感染和主要原因。一个关键问题是，我们对谁会患上肺炎只有一个粗略的概念，因此无法采取针对性的预防措施。这项研究的目标是开发一种基于临床检查和血液测试的风险预测工具，该工具可以作为常规检查的一部分进行，以识别肺炎高危人群。