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: 9108422
• 负责人: Noah A Zaitlen
• 金额: $ 17.16万
• 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/9108422
• 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; Genetic study; Genomics; Goals; Health; Heritability; Hispanics; Immune response; Immunologics; Immunology; Individual; Laboratories; Latino; Lead; Learning; Life; Lung; Lung diseases; Measurement; Measures; Medical Genetics; 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; asthmatic; base; career; cohort; design; disease phenotype; disorder risk; environmental agent; ethnic difference; ethnic diversity; gene environment interaction; genetic association; genetic variant; genome wide association study; genome-wide; improved; interdisciplinary collaboration; non-genetic; novel; professor; programs; 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）：更丰富的哮喘风险模型：弥合环境-遗传学鸿沟。这是一个指导定量研究开发奖（K25）的应用程序，诺亚Zaitlen博士，助理教授在加州大学旧金山分校弗朗西斯科医学系，肺生物学中心。Zaitlen博士在生物信息学和计算遗传学领域已经成为一名成功的年轻研究人员。他最近接受了UCSF的教职，目的是建立一个独立的实验室，致力于研究肺部疾病的遗传和环境基础，重点是拉丁裔和非洲裔美国人。拟议的K25奖将为Zaitlen博士提供支持和保护时间，以实现以下目标：（1）通过课程工作和指导导师培养足够的肺部医学背景，以构建遗传和环境变量的哮喘风险模型;（2）培养免疫学和环境健康方面的专业知识，特别是与肺部表型相关的知识;（3）研究哮喘的遗传、环境和种族变异之间的关系;（4）培养形成大规模跨学科合作的技能; 最终目标是（5）发展独立的研究事业。Zaitlen博士组建了一个指导团队，由主要导师，UCSF哮喘遗传学实验室主任Esteban Gonzalez Burchard博士，研究环境健康的共同导师John Balmes博士和研究哮喘亚表型的Prescott Woodruff博士以及顾问Neal Risch博士，Saunak Sen和John Witte博士组成，他们都成功地从定量背景过渡到生物医学研究。 哮喘是一种常见的复杂疾病，发病率高，往往在生命早期发作。家庭和双胞胎研究明确指出遗传易感性，但流行病学也强烈表明重要的环境风险因素。有大量的种族差异尚未得到解释，也不完全符合简单的遗传或环境解释（即两个拉丁美洲群体，墨西哥人和波多黎各人的比例最不相同）。 因此，为了更好地了解哮喘的发病机制，需要采取多管齐下的方法，将免疫学，肺生物学和环境健康以及遗传易感性的基本理解结合起来。虽然Zaitlen博士精通统计遗传学，但他在统计遗传学方面就差得多了。 上面提到的其他重要学科。 Burchard博士的指导和对他在拉丁裔人群中哮喘研究的访问为Zaitlen博士制定他的研究计划提供了一个独特的机会。关于这些主题的详细临床，遗传和环境信息不仅为同时建模遗传和环境风险因素提供了丰富的资源，而且还需要Zaitlen博士在Balmes博士的帮助下学习环境流行病学的基础知识。此外，这些受试者的标本沿着来自Dr. Woodruff队列的标本将用于相关免疫学和基因组测定，以更直接地解决疾病途径。在伍德拉夫博士的指导下进行的这个实验部分为Zaitlen博士提供了免疫学方面的培训，并大大拓宽了他未来研究项目的范围。未来的试验可能包括免疫功能，宿主对环境暴露的反应，如通过表观遗传和表达水平研究所表现的，以及对抗原剂的细胞反应的其他直接试验。 到目前为止，在遗传方面，哮喘的全基因组关联研究仅具有部分启发性。他们指出了一些重要的候选基因，但同时反映了一般的观察结果，即变异如何导致疾病风险的机制是未知的。由于发病机制取决于遗传易感性和环境暴露之间的相互作用，最终需要复杂的系统生物模型来充分理解这些关系。这样的模型大大增强了测量的“中间”表型，更直接的因果关系相关的潜在基因和环境因素比坦率的疾病。这些方法将利用Zaitlen博士强大的计算背景，但也需要充分了解免疫学，肺生物学和宿主对环境暴露的反应。 有了这个奖项所提供的保护时间，Zaitlen博士最终创建的模型不会仅仅因为他的统计敏锐性而变得更好。他将对基础生物学有必要的了解，并在设计检测方法方面接受技术培训，以指导一项涵盖实验和计算工作的全面哮喘研究计划。