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）：更丰富的哮喘风险模型：弥合环境-遗传学鸿沟。这是加州大学旧金山分校医学系肺生物中心助理教授 Noah Zaitlen 博士申请指导定量研究发展奖 (K25) 的申请。 Zaitlen 博士已成为生物信息学和计算遗传学领域一位成功的年轻研究者。他最近接受了加州大学旧金山分校的教职，目标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，重点关注拉丁裔和非裔美国人。拟议的 K25 奖项将为 Zaitlen 博士提供支持和受保护的时间，以实现以下目标：（1）通过课程作业和指导指导培养足够的肺医学背景，以构建针对遗传和环境变量的哮喘风险模型； (2) 发展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专业知识； (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、加州大学旧金山分校哮喘遗传学实验室主任 Esteban Gonzalez Burchard 博士、研究环境健康的 John Balmes 博士和研究哮喘亚表型的 Prescott Woodruff 博士组成。和顾问博士。 Neal Risch、Saunak Sen 和 John Witte 都成功地从定量背景转向了生物医学研究。 哮喘是一种常见且复杂的疾病，发病率很高，通常在生命早期发病。家庭和双胞胎研究清楚地指出了遗传易感性，但流行病学也强烈表明了重要的环境风险因素。存在尚未解释的重大种族差异，并且与简单的遗传或环境解释并不完全一致（即两个拉丁裔群体，墨西哥人和波多黎各人的比率差异最大）。 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，结合对免疫学、肺生物学、环境健康以及遗传易感性的基本了解。虽然 Zaitlen 博士精通统计遗传学，但他在统计遗传学方面却知之甚少。 上述其他重要学科。 Burchard 博士的指导和他对拉丁裔人群哮喘的研究为 Zaitlen 博士制定他的研究计划提供了独特的机会。这些主题的详细临床、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，这些受试者的样本以及伍德拉夫博士团队的样本将用于相关的免疫学和基因组检测，以更直接地解决疾病的途径。该实验部分是在 Woodruff 博士的指导下进行的，为 Zaitlen 博士提供了免疫学方面的培训，并显着拓宽了他未来研究项目的范围。未来的检测可能包括免疫功能、宿主对环境暴露的反应（通过表观遗传和表达水平研究表明），以及细胞对抗原剂反应的其他直接检测。 迄今为止，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，但同时反映了普遍的观察结果，即变异如何影响疾病风险的机制尚不清楚。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，因此最终需要复杂的系统生物模型来充分理解这些关系。通过纳入测量的“中间”表型，这些模型得到了极大的增强，这些表型与潜在的基因和环境因素比直接疾病有更直接的因果关系。这些方法将利用 Zaitlen 博士强大的计算背景，但也需要对免疫学、肺部生物学和宿主对环境暴露的反应有基本的了解。 在该奖项提供的受保护时间下，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。他将具备对基础生物学所需的了解以及设计检测的技术培训，以指导涵盖实验和计算工作的综合哮喘研究计划。