Richer Models of Asthma Risk: Bridging the Environment-Genetics Divide

更丰富的哮喘风险模型：弥合环境-遗传学鸿沟

• 批准号: 8767169
• 负责人: Noah A Zaitlen
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767169
• 关键词: Accounting; Address; Adolescent; African; African American; Age; Air; Allergens; Americas; Asthma; Award; Bioinformatics; Biological Assay; Biological Models; Biology; Biomedical Research; Bronchial Lavages; Candidate Disease Gene; Cellular Assay; Classification; Clinical; Communities; Complex; Data; Data Set; Discipline; Disease; Disease model; Employee Strikes; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemic; Epidemiology; Epigenetic Process; Ethnic Origin; European; Exposure to; Faculty; Family Study; Fostering; Future; GALA; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genetic Variation; Genomics; Goals; Health; Heritability; Hispanics; Immune response; Immunologics; Immunology; Individual; Laboratories; Latino; Lead; Learning; Life; Lung; Lung diseases; Measurement; Measures; Medicine; Mentors; Mentorship; Methods; Methylation; Mexican; Modeling; Molecular Profiling; Morbidity - disease rate; Names; Nature; Outcome; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Prevalence; Public Health; Puerto Rican; Pulmonology; RNA Sequences; Research; Research Personnel; Resources; Risk; Role; San Francisco; Side; Smoking; Sorting - Cell Movement; Specimen; System; Techniques; Th2 Cells; Time; Training; Twin Studies; Variant; Work; base; career; cohort; design; disease phenotype; disorder risk; environmental agent; ethnic difference; gene environment interaction; genetic association; genetic variant; genome wide association study; genome-wide; improved; interdisciplinary collaboration; non-genetic; novel; professor; programs; public health relevance; research and development; response; risk variant; segregation; skills; tool

DESCRIPTION (provided by applicant): Richer Models of Asthma Risk: Bridging the Environment-Genetics Divide. This is an application for a Mentored Quantitative Research Development Award (K25) for Dr. Noah Zaitlen, an Assistant Professor in the UC San Francisco Department of Medicine, Lung Biology Center. Dr. Zaitlen has established himself as a successful young investigator in the fields of bioinformatics and computational genetics. He has recently accepted at faculty position at UCSF with the aim of establishing an independent laboratory dedicated to the study of the genetic and environmental basis of pulmonary disease with a focus on Latino and African American populations. The proposed K25 award would provide Dr. Zaitlen with support and protected time to accomplish the following goals: (1) develop via course-work and guided mentorship a sufficient background in pulmonary medicine to construct asthma risk models over genetic and environmental variables; (2) develop an expertise in immunology and environmental health, especially as they relate to pulmonary phenotypes; (3) conduct research into the relationship between genetic, environmental, and ethnic variation in asthma; (4) foster skills to form large-scale interdisciplinary collaborations; with an ultimate goal of (5) developing an independent research career. Dr. Zaitlen has assembled a mentoring team comprised of a primary mentor, Dr. Esteban Gonzalez Burchard, Director of the Asthma Genetics Laboratory at UCSF, co-mentors Dr. John Balmes who studies environmental health, and Dr. Prescott Woodruff who studies asthma subphenotypes, and advisors Drs. Neal Risch, Saunak Sen, and John Witte who all successfully transitioned from quantitative backgrounds into biomedical research. Asthma is a common and complex disease with significant morbidity, often striking early in life. Family and twin studies clearly point to genetic susceptibility, but the epidemiology also strongly indicates important environmental risk factors. There are substantial ethnic differences that are not yet explained - and not entirely consistent with a simple genetic or environmental explanation (i.e. the two Latino groups, Mexicans and Puerto Ricans have the most disparate rates). To better understand the pathogenesis of asthma therefore requires a multi-pronged approach, bringing together basic understanding of immunology, lung biology and environmental health as well as genetic susceptibility. While Dr. Zaitlen is well versed in statistical genetics, he is much less so in the other important disciplines named above. Dr. Burchard's mentorship and access to his studies of asthma in Latino populations offer a unique opportunity for Dr. Zaitlen to develop his research plans. The detailed clinical, genetic and environmental information on these subjects will not only provide a rich resource for simultaneously modeling genetic and environmental risk factors, but will require Dr. Zaitlen, with the help of Dr. Balmes, to learn the fundamentals of environmental epidemiology. Furthermore, the specimens from these subjects along with those from Dr. Woodruff's cohorts will be used for relevant immunological and genomic assays that more directly address the pathways to disease. This experimental component, conducted under the mentorship of Dr. Woodruff, provide Dr. Zaitlen with training in immunology as well as significantly broadening the scope of his future research projects. Future assays may include immunologic function, host response to environmental exposures as manifest through epigenetic and expression level studies, and other direct assays of cellular response to antigenic agents. To date, on the genetic side, genome-wide association studies of asthma have only been partially enlightening. They have indicated some important candidate genes, but at the same time reflect the general observation that the mechanism of how variants contribute to disease risk is unknown. Because pathogenesis depends on an interaction between genetic susceptibility and environmental exposure, complex systems biologic models ultimately are required to fully understand these relationships. Such models are greatly enhanced by the inclusion of measured 'intermediate' phenotypes that are more directly causally related to the underlying genes and environmental agents than frank disease. These approaches will capitalize on Dr. Zaitlen's strong computational background, but also need to be well informed by a basic understanding of immunology, lung biology and host responses to environmental exposures. With the protected time afforded by this award, the models Dr. Zaitlen ends up creating will not be better simply because of his statistical acumen. He will have the required understanding of the underlying biology as well the technical training in designing assays to direct a comprehensive asthma research program spanning experimental and computational work.

描述（由申请人提供）：哮喘风险的更丰富的模型：桥接环境基因分歧。这是申请指导的定量研究开发奖（K25），该奖项是肺部生物学中心加州大学旧金山加州大学旧金山加州大学旧金山分校助理教授诺亚·扎特伦（Noah Zaitlen）博士。 Zaitlen博士已在生物信息学和计算遗传学领域成为成功的年轻研究者。他最近在UCSF的教师职位上接受了一个独立的实验室，该实验室致力于研究肺部疾病的遗传和环境基础，重点是拉丁裔和非裔美国人人口。拟议的K25奖将为Zaitlen博士提供支持和受保护的时间，以实现以下目标：（1）通过课程工作和指导指导发展肺部医学的足够背景，以在遗传和环境变量上构建哮喘风险模型； （2）发展免疫学和环境健康方面的专业知识，尤其是与肺部表型相关的专业知识； （3）对哮喘的遗传，环境和种族变异之间的关系进行研究； （4）培养大型跨学科合作的技能； 最终的目标是（5）发展独立的研究职业。 Zaitlen博士召集了一支由主要导师组成的指导团队，UCSF的哮喘遗传学实验室主任Esteban Gonzalez Burchard博士，研究环境健康的John Balmes博士和研究Asthma Asphenotypes和Advisors Drs的Prescott Woodruff博士。 Neal Risch，Saunak Sen和John Witte都成功地从定量背景过渡到了生物医学研究。 哮喘是一种常见且复杂的疾病，具有明显的发病率，通常在生命的早期就引人注目。家庭和双胞胎研究清楚地表明了遗传易感性，但是流行病学也强烈表明了重要的环境风险因素。尚未解释存在实质性的种族差异，并且与简单的遗传或环境解释完全不一致（即两个拉丁裔群体，墨西哥人和波多黎各人的差异最高）。 因此，为了更好地了解哮喘的发病机理需要一种多管齐的方法，将对免疫学，肺部生物学和环境健康以及遗传敏感性的基本理解汇总在一起。尽管Zaitlen博士精通统计遗传学，但他在 上述其他重要学科。 Burchard博士的指导和对拉丁裔人口哮喘的研究的机会为Zaitlen博士提供了独特的机会制定了他的研究计划。这些受试者的详细临床，遗传和环境信息不仅将为同时建模遗传和环境风险因素提供丰富的资源，而且还需要在Balmes博士的帮助下Zaitlen博士学习环境流行病学的基础。此外，这些受试者的标本以及伍德拉夫博士同类的标本将用于相关的免疫和基因组测定，这些试验更直接地解决了疾病的途径。在伍德拉夫（Woodruff）博士的指导下进行的这个实验组成部分为Zaitlen博士提供了免疫学培训，并显着扩大了他未来的研究项目的范围。未来的测定可能包括免疫功能，通过表观遗传学和表达水平研究表现为对环境暴露的宿主反应，以及其他直接对抗原剂反应的直接测定。 迄今为止，在遗传方面，哮喘的全基因组关联研究仅是部分启发性的。他们已经指出了一些重要的候选基因，但同时反映了一个普遍的观察，即变体如何促进疾病风险的机制尚不清楚。由于发病机理取决于遗传易感性与环境暴露之间的相互作用，因此最终需要复杂的系统生物模型才能充分理解这些关系。与弗兰克病相比，与基础基因和环境药物更直接相关的测量“中间”表型可以极大地增强此类模型。这些方法将利用Zaitlen博士的强大计算背景，但还需要通过对免疫学，肺部生物学和宿主对环境暴露的反应的基本了解来充分了解。 随着该奖项提供的受保护时间，Zaitlen博士最终创建的模型仅仅是因为他的统计敏锐度就不会更好。他将对基础生物学有必要的理解，以及设计测定法的技术培训，以指导一项涵盖实验和计算工作的全面哮喘研究计划。