Genetic epidemiology of TLR4 alleles and bacteremia

TLR4 等位基因和菌血症的遗传流行病学

• 批准号: 6764049
• 负责人: JASON W CHIEN
• 金额: $ 15.53万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764049
• 关键词: bacteria infection mechanism; bacterial disease; clinical research; family genetics; gene environment interaction; gene interaction; genetic polymorphism; genetic susceptibility; gram negative bacteria; human genetic material tag; human population genetics; human subject; immunogenetics; patient oriented research; toll like receptor

DESCRIPTION (provided by applicant): This award will provide an opportunity for the Principal Investigator (PI) to develop as an independent patient-oriented scientific investigator in the field of human genome epidemiology. By pursuing didactic course work in genetic epidemiology and acquiring skills in molecular genetic laboratory techniques, the PI will become a properly trained genetic epidemiologist with an in-depth understanding of the technical aspects of molecular genetics. This will ultimately lead to a successful independent research career focused upon understanding the genetic determinants of pathogen recognition, the host immune response, and the clinical diseases associated with exposure to invading pathogens and their products. The primary scientific goal of this proposal is to determine the association between the toll-like receptor 4 (TLR4) polymorphisms and gram-negative (GN) bacteremia. Aim I will use samples from a genetic repository derived from stem cell transplant patients and donors. A case-control study will identify any potential association between the null TLR4 alleles and acquiring GN bacteremia. This study will also provide a unique insight into gene environment and gene-gene interaction with the tumor necrosis factor-alpha (TNF-cc) polymorphisms. In addition, we will examine whether the TLR4 alleles effect the host immune response, measured clinically by acute physiology scores. Aim 2 will be a prospective family-based genetic study lasting the duration of this funding period. Initial laboratory studies will focus on development of an ex vivo lipopolysaccharide (LPS) hyporesponsive phenotype through the use of whole blood culture assays. The phenotype will be identified for each hematopoietic stem cell or bone marrow transplant patient. Genetic information from the patient, parents, and siblings, will then be used in a transmission disequilibrium test to determine whether the TLR4 polymorphisms are associated and genetically linked to the ex vivo LPS hyporesponsive phenotype. Ultimately, this cohort of patients will be developed in anticipation of future genetic discoveries in the complicated pathway of pathogen recognition and host inflammatory response.

描述（由申请人提供）： 该奖项将为首席调查员（PI）提供机会 发展为独立的以患者为导向的科学研究者 人类基因组流行病学领域。通过从事教学课程工作 遗传流行病学和分子遗传实验室技能 技术，PI将成为经过适当训练的遗传流行病学家 对分子遗传学技术方面的深入了解。 这最终将导致以成功的独立研究职业为重点 了解病原体识别的遗传决定因素后，宿主 免疫反应以及与暴露有关的临床疾病 入侵病原体及其产品。此的主要科学目标 建议是确定Toll样受体4之间的关联 （TLR4）多态性和革兰氏阴性（GN）菌血症。目的我会使用 来自源自干细胞移植患者的遗传存储库的样品 和捐助者。病例对照研究将确定任何潜在关联 在零TLR4等位基因和获得GN菌血症之间。这项研究会 还提供有关基因环境和基因相互作用的独特见解 与肿瘤坏死因子-Alpha（TNF-CC）多态性。另外，我们 将检查TLR4等位基因是否影响宿主免疫反应， 通过急性生理评分在临床上测量。 AIM 2将是一个准 基于家庭的遗传研究持续了这一融资期的持续时间。 最初的实验室研究将集中于实体的发展 脂多糖（LPS）通过整体使用 血液培养测定法。每个造血的表型将被确定 干细胞或骨髓移植患者。来自 病人，父母和兄弟姐妹将用于传播 不平衡测试以确定TLR4多态性是否相关 并在遗传上与体内LPS的低回避表型相关。 最终，将开发这一组患者，以期预期 病原体识别的复杂途径中的未来遗传发现 和宿主炎症反应。