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: 6652507
• 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/6652507
• 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）： 该奖项将为首席研究员（PI）提供一个机会 发展成为一名以患者为中心的独立科学研究者 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学实验室技能获取 技术，PI 将成为一名经过适当培训的遗传流行病学家 对分子遗传学技术方面的深入了解。 这最终将带来成功的独立研究生涯 在了解病原体识别的遗传决定因素后，宿主 免疫反应以及与接触相关的临床疾病 入侵的病原体及其产物。本次研究的主要科学目标 建议确定 Toll 样受体 4 之间的关联 (TLR4) 多态性和革兰氏阴性 (GN) 菌血症。我将使用的目标 来自干细胞移植患者遗传库的样本 和捐助者。病例对照研究将确定任何潜在的关联 TLR4 无效等位基因与获得 GN 菌血症之间的差异。这项研究将 还提供对基因环境和基因间相互作用的独特见解 具有肿瘤坏死因子-α (TNF-cc) 多态性。此外，我们 将检查 TLR4 等位基因是否影响宿主免疫反应， 通过急性生理学评分进行临床测量。目标2将是一个前瞻性的 以家庭为基础的基因研究持续本资助期间。 最初的实验室研究将集中于离体开发 通过使用全脂多糖（LPS）低反应表型 血培养测定。将鉴定每个造血系统的表型 干细胞或骨髓移植患者。遗传信息来自 患者、父母和兄弟姐妹，然后将用于传输 不平衡测试以确定 TLR4 多态性是否相关 并与离体 LPS 低反应表型有遗传联系。 最终，这组患者的开发将预期 病原体识别复杂途径中的未来遗传发现 和宿主炎症反应。