Genetic and Environmental Determinants of Food Allergy

描述(由申请人提供)：这项K23奖项将为Corinne Keet，医学博士，MS，提供必要的培训和经验，成为一名在过敏和免疫学领域进行以患者为导向的研究的独立调查员。在这项提案中，Keet博士将研究食物过敏(FA)的关键环境和遗传风险因素，FA是一种常见疾病，环境和遗传决定因素基本上未知。虽然长期以来一直观察到湿疹倾向于导致FA，但为什么会出现这种情况尚不清楚。Keet博士之前的工作表明，紫外线和维生素D可能会改变这种关系，因为它表明湿疹和坠落分娩相互作用，增加了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，它可能如何与秋季出生相互作用，以及维生素D途径如何在FA中发挥作用。具体地说，Keet博士将测试以下假设：皮肤屏障功能障碍的遗传易感性会增加FA的风险，这可能会因秋季出生而改变，秋季出生会增加皮肤屏障功能障碍的风险(目标1)，以及维生素D途径与FA相关，与秋季出生相互作用，以及秋季出生导致生命早期维生素D减少(目标2)。为了实现这些目标，基特博士将使用已经建立的以家庭为基础的大型食物过敏患者队列和新的3个月大婴儿队列。基特博士组建了一支拥有深厚和多样化专业知识的导师团队。王晓斌博士是首席导师，他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，并在指导年轻研究人员在学术医学领域取得成功方面有着良好的记录。罗伯特·伍德博士除了在临床研究方面拥有丰富的经验外，还带来了儿科过敏方面的专业知识。特里·比蒂博士是遗传流行病学专家，英戈·鲁津斯基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、资源和专业知识来促进基特博士的职业发展。这项K23奖项还将为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，这将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命决定因素研究方面的成功至关重要。这位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，她完成了流行病学硕士学位。然后，她完成了儿科住院医生的工作，并在约翰霍普金斯大学获得了儿科过敏和免疫学方面的奖学金。在伍德博士的指导下，她在研究员期间进行了一项牛奶过敏免疫疗法的临床试验，证明口服免疫疗法比舌下免疫疗法更有效，而且超过两年的治疗所取得的脱敏效果可能很快就会消失。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年作为儿科助理教授加入约翰霍普金斯大学时，她报名参加了JHBSPH的流行病学博士项目。从那时起，她作为一名临床研究学者得到了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谨课程，同时启动了国家过敏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，以使基特博士成为过敏性疾病流行病学方面的专家，包括这些疾病的遗传流行病学。经过临床研究、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得天独厚的优势。这里描述的培训和产生的数据将提供必要的基础，以竞争NIH的R01拨款，并作为儿童早期过敏疾病决定因素的专家建立独立的职业生涯。相关性：在美国，FA影响了大约5%的儿童，但其原因在很大程度上是未知的。这项工作的结果可能会为预防FA的策略提供参考。这一K23奖项的目标是为Corinne Keet，MD，MS提供一个培训平台，使其成为一名独立调查员，在过敏和免疫学领域进行以患者为中心的研究，并探索食物过敏的发展机制，食物过敏是一种影响约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。这项研究的发现可能为食物过敏的预防策略提供参考。

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.