PROJECT SUMMARY/ABSTRACT Dr. Mey is a productive young scientist applying for this mentored K01 award to transition to an independent research career. He has a strong nutrition (registered dietitian) and metabolism (translational research) background, focusing on metabolic disease. He has a history of growth and productivity throughout the evolution of his research career into his current role as an assistant professor. His recent findings have directed his interest towards a major literature gap: the impact of nutrition on asthma control and lung function – relevant to the mission of NHLBI. An emerging concept in asthma pathophysiology is altered nutrient metabolism and mitochondrial bioenergetics. Nutritional intake has a direct impact on whole-body and cellular nutrient metabolism, and several nutritional approaches show promise to improve lung function. However, well-controlled feeding trials are lacking, leaving a major knowledge gap in our understanding of nutrition in asthma. Further, nutrition research has come under intense scrutiny for major barriers, including inter-individual variability, slow development and poor translation to clinical application. To address this important knowledge gap and overcome critical barriers in nutrition research, the proposed aims will utilize an innovative multi-diet crossover clinical feeding trial design in combination with an n-of-1 qualitative pilot. The feeding trial will test three distinct, fully-provided, isocaloric diets to identify nutritional and metabolic factors that impact asthma control and lung function. This will be followed by a qualitative pilot of an n-of-1 approach, which incorporates patient- informed decisions into the nutrition treatment model and is critical to the progression of individualized nutrition care. Additionally, untargeted plasma metabolomic profiling will be used in combination with machine-learning biostatistics to generate preliminary precision nutrition models for future clinical research. Finally, an in vitro approach will define the mitochondrial defects in airway smooth muscle cells from an asthmatic donor and determine whether chronic ketone exposure can normalize altered mitochondrial bioenergetics. Together, the clinical findings, qualitative pilot and elucidation of a biological mechanism defining the diet-asthma relationship will support Dr. Mey’s transition to independence. To enable Dr. Mey to carry out these aims and transition his nutrition and metabolism expertise into the pulmonary field, Dr. Mey has enlisted the mentorship of 5 established researchers and clinicians for the fulfillment of the training detailed within this project, including: 1) academic and professional development in asthma and mitochondrial biology, 2) clinical management of asthma, 3) support to implement a multi-diet crossover feeding trial, and 4) career development and grant writing guidance. In addition, Dr. Mey assembled a team of 4 collaborators and advisors for technical and scientific insight. Pennington Biomedical Research Center will provide an ideal learning environment, with exceptional core services to conduct clinical trials, supplemented by training with physician-mentors both locally (Tulane) and abroad (Cleveland Clinic). Together, this coordinated clinical-translational training will provide Dr. Mey with the tools to complete the proposed aims, expand his expertise of nutrition and metabolism into the pulmonary field, and establish independence in the pursuit of his long-term goal: to identify precision nutrition approaches for the treatment and management of asthma.

PROJECT NARRATIVE Despite the profound prevalence of asthma, we do not yet have a defined nutritional approach to support disease management. This research will elucidate a novel relationship between how diet effects asthma symptoms and lung function through altering the way our cells use energy. The short-term impact is new fundamental knowledge on the connection between diet, cellular energetics and asthma, while the long- term impact will open new lines of research aimed at using nutrition to improve the treatment and management of asthma, which may elevate patient care and quality of life for individuals with asthma.