This K08 proposal describes a comprehensive training program tailored to the career development of the candidate. The candidate is a physician who recently completed a clinical fellowship in Allergy and Immunology and whose research contributions to date have addressed early-life risk factors for childhood asthma and allergy with a focus on the diet and intestinal microenvironment. Asthma and environmental allergies have increased in prevalence and asthma is now the most common chronic disease in children. The increased occurrence of asthma and allergy has been attributed to changes including dietary shifts and dysbiosis, though contributory factors are incompletely defined and interventions to prevent asthma and allergy remain elusive. Polyunsaturated fatty acids (PUFA), including omega-3 and omega-6 fatty acids (FA) have well-defined immunologic effects, and the ratio of omega-6:omega-3 FA intake has increased concurrently with the increase in allergic disease. However, reported associations of PUFA with asthma and allergy in childhood are inconsistent. The overarching hypothesis of this proposal is that effects of PUFA are impacted by host genotype and the intestinal microbiota. Our scientific goal is to examine these omics to identify determinants of when a safe and inexpensive intervention, intake of PUFA, is effective in reducing asthma and allergy in childhood. We will utilize data from 6- and 7-year-old participants in three study populations: Vitamin D Antenatal Asthma Reduction Trial (VDAART), Project Viva and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). We have three specific aims: (1) Identify gene by omega-3 FA interactions in asthma and allergy in childhood; (2): Define the contributions of intestinal bacteria and metabolites to associations of omega-3 FA dietary intake with asthma and allergy in childhood; and (3) Characterize clinically relevant childhood plasma PUFA profiles using unsupervised classification methods and integrative machine learning algorithms. Our findings could lead to cost-effective and personalized approaches to asthma and allergy reduction by elucidating which individuals benefit from dietary PUFA supplementation and whether microbiota-modifying therapies could boost protective responses to PUFA. The candidate proposes to execute this research plan alongside a training and development plan including hands-on bioinformatics instruction and preparation for independent mechanistic and clinical R01-level follow-up projects. The proposed work will be mentored by Dr. Scott Weiss, a Professor at Harvard Medical School and a leader in environmental, nutritional and genetic asthma risk factors. The candidate will obtain additional scientific input and career guidance from a team including a co-mentor and three scientific advisors with expertise in asthma epidemiology, lipid mediators of allergic inflammation, multi-omics analysis and translational research methods. This proposal represents a natural continuation of the candidate?s prior experience and will provided the support needed for her to become an independent investigator with a focus on precision medicine approaches to asthma and allergy.
Polyunsaturated fatty acids (PUFA) are dietary fats with effects on immune function and inflammation, and the genes that a person is born with or the bacteria that live in one?s gut could influence how the body processes and responds to PUFA. We will study children to see if having particular gene variants or specific gut bacteria or chemicals impacts how PUFA intake relates to risk of asthma and allergy. Understanding how genetic, microbial, and other factors influence PUFA processing and asthma and allergies could lead to new cost- effective ways to prevent and treat these increasingly common and clinically burdensome diseases.
