Genetic and Environmental Determinants of Food Allergy

描述（由申请人提供）：这个K23奖将为Corinne Keet， MD， MS，提供必要的培训和经验，成为一名独立的研究者，在过敏和免疫学领域进行面向患者的研究。在本提案中，Keet博士将研究食物过敏（FA）的关键环境和遗传风险因素，这是一种常见疾病，其环境和遗传决定因素在很大程度上未知。虽然长期以来人们一直观察到湿疹倾向于导致FA，但原因尚不清楚。Keet博士之前的研究表明，紫外线和维生素D可能会改变这种关系，表明湿疹和早产相互作用会增加患FA的风险。在这里，Keet博士将探讨对皮肤屏障损伤的易感性在FA中的作用，它如何与早产相互作用，以及维生素D途径如何在FA中发挥作用。具体来说，Keet博士将测试以下假设：皮肤屏障功能障碍的遗传易感会增加FA的风险，这可能会被秋产所改变，秋产会增加皮肤屏障功能障碍的风险（目的1）；维生素D途径与FA相关，与秋产相互作用，秋产会导致生命早期维生素D减少（目的2）。为了实现这些目标，Keet博士将使用一个已经建立的以家庭为基础的食物过敏患者队列和一个新的3个月大的婴儿队列。基特博士组建了一个具有深厚和多样化专业知识的指导团队。主要导师王晓斌博士在儿童早期疾病决定因素的研究、队列的建立和维护方面拥有深厚的专业知识，并在指导年轻研究者在学术医学领域取得成功方面有着良好的记录。罗伯特伍德博士带来了儿科过敏的专业知识，除了丰富的临床研究经验。Terri Beaty博士是遗传流行病学方面的专家，Ingo Ruczinski博士专门从事基因组研究的分析。所有这些导师都承诺他们的时间、资源和专业知识，以促进Keet博士的职业发展。K23奖还将为Keet博士提供接受流行病学高级培训的机会，包括在约翰霍普金斯大学彭博公共卫生学院（JHBSPH）完成流行病学博士学位，这对该项目的成功以及她未来在以患者为导向的过敏性疾病早期生活决定因素研究方面的成功至关重要。候选人过去的经历表明她致力于学术医学事业，并有能力在该领域取得成功。在医学院期间，她获得了流行病学硕士学位。随后，她在约翰霍普金斯大学完成了儿科住院医师和儿科过敏和免疫学的奖学金。在Wood博士的指导下，在研究期间，她进行了一项免疫治疗牛奶过敏的临床试验，证明口服免疫治疗比舌下免疫治疗更有效，并且在2年的治疗中取得的脱敏效果可能会迅速消失。在此期间，她还对与过敏性疾病发展相关的更广泛的问题产生了兴趣，当她于2010年加入约翰霍普金斯大学担任儿科助理教授时，她参加了JHBSPH的流行病学博士课程。从那时起，她作为临床研究学者获得了KL2奖的支持，并完成了流行病学、生物统计学和遗传流行病学的严格课程，同时开始了国家变态反应性疾病流行病学的研究项目。目前的建议建立在这些经验的基础上，并提供额外的指导，以使Keet博士成为过敏性疾病的流行病学专家，包括这些疾病的遗传流行病学。在临床研究，流行病学和过敏/免疫学方面的培训，候选人在进行这些研究方面具有独特的优势。这里描述的培训和产生的数据将为竞争NIH的R01拨款提供必要的基础，并建立一个独立的职业生涯，作为儿童早期过敏性疾病决定因素的专家。相关性：在美国，大约有5%的儿童患有FA，但其病因在很大程度上是未知的。这项工作的结果可能为预防FA的策略提供信息。K23奖的目标是为Corinne Keet， MD， MS提供一个培训平台，使其成为一名独立的研究者，在过敏和免疫学领域进行以患者为导向的研究，并探索食物过敏的发展机制，这是一种影响约5%儿童的疾病。在两个儿科队列中，我们将研究(1)食物过敏的两个候选基因途径，皮肤屏障和维生素D，(2)这些途径与出生季节之间的相互作用，以及(3)出生季节对早期生命皮肤屏障和维生素D的影响。本研究的结果可能为食物过敏的预防策略提供信息。

DESCRIPTION (provided by applicant): This K23 award will provide Corinne Keet, MD, MS, with the necessary training and experience to become an independent investigator performing patient-oriented research in the field of allergy and immunology. In this proposal, Dr. Keet will study key environmental and genetic risk factors for food allergy (FA), a common disease with largely unknown environmental and genetic determinants. Although it has long been observed that eczema tends to lead to FA, why this is the case is unknown. Previous work by Dr. Keet suggested that UV light and vitamin D may alter this relationship, by showing that eczema and fall birth interacted to increase the risk of FA. Here, Dr. Keet will explore the role of susceptiblity to skin barrier impairment in FA, how it may interact with fall birth, and how the vitamin D pathway may play a role in FA. Specifically, Dr. Keet will test the hypotheses that genetic predisposition to skin barrier dysfunction increases risk of FA, that this may be modified by fall birth, and that fall birth increases the risk of skin barrier dysfunction (Aim 1), and the hypothess that the vitamin D pathway is associated with FA, interacts with fall birth, and that fall birth leds to decreased vitamin D in early life (Aim 2). To accomplish these aims, Dr. Keet will use both an already established large family-based cohort of food allergic patients and a new cohort of 3 month old infants. Dr. Keet has assembled a mentorship team with deep and diverse expertise. Dr. Xiaobin Wang, the primary mentor, brings deep expertise in the study of early childhood determinants of disease, the establishment and maintenance of cohorts, and has a strong track record of mentoring young investigators for successful careers in academic medicine. Dr. Robert Wood brings expertise in pediatric allergy, in addition to extensive experience in clinical research. Dr. Terri Beaty is an expert in genetic epidemiology, and Dr. Ingo Ruczinski specializes in the analysis of genomic studies. All of these mentors have pledged their time, resources and expertise to facilitate Dr. Keet's career development. This K23 award will also provide Dr. Keet with opportunities for advanced training in epidemiology, including the completion of a PhD in Epidemiology at the Johns Hopkins Bloomberg School of Public Health (JHBSPH), which will be essential to the success of this project and to her future success in patient-oriented research of the early life determinants of allergic disease. The candidate's past experiences illustrate her commitment to a career in academic medicine and ability to be successful in this field. During medical school, she completed a Masters focusing on epidemiology. She then completed pediatric residency and a fellowship in Pediatric Allergy and Immunology at Johns Hopkins. Under the mentorship of Dr. Wood, during fellowship she conducted a clinical trial of immunotherapy for milk allergy, demonstrating that oral immunotherapy was more effective that sublingual, and that desensitization achieved over 2 years of treatment could be rapidly lost. During this time she also became interested in broader questions related to the development of allergic disease, and when she joined the faculty at Johns Hopkins as an Assistant Professor of Pediatrics in 2010, she enrolled in a PhD program in Epidemiology at the JHBSPH. Since that time, she has been supported by a KL2 award as a clinical research scholar, and has completed rigorous coursework in epidemiology, biostatistics and genetic epidemiology, while starting research projects on the national epidemiology of allergic disease. The current proposal builds on these experiences with additional mentorship to establish Dr. Keet as an expert in the epidemiology of allergic diseases, including genetic epidemiology of these diseases. With training in clinical research, epidemiology and allergy/immunology, the candidate is uniquely positioned to conduct these studies. The training described here, and the data generated, will provide a foundation needed to compete for a R01 grant from the NIH and establish an independent career as an expert in the early childhood determinants of allergic disease. Relevance: FA affects approximately 5% of children in the U.S., but the causes are largely unknown. The results of this work may inform strategies to prevent FA. The goals of this K23 award are to provide a training platform for Corinne Keet, MD, MS to become an independent investigator performing patient-oriented research in the field of allergy and immunology, and to explore the mechanisms of the development of food allergy, a disease that affects approximately 5% of children. In two pediatric cohorts, we will examine (1) two candidate gene pathways for food allergy, the skin barrier and vitamin D, (2) interactions between these pathways and season of birth, and (3) the effects of season of birth on early life skin barrier and vitamin D. The findings from this study may inform preventative strategies for food allergy.