Investigating the role of gene regulatory networks in neonatal nutrition and immunity - PROJECT SUMMARY The neonatal period of life is a critical time of rapid development. To fuel this growth, the neonatal intestine must selectively absorb nutrients while establishing an immune defense against lumenal pathogens. These two core functions are intimately linked, as impaired nutrition early in life impairs systemic immune function. However, the connections between neonatal nutrient uptake and immune development remain poorly understood. Unlike adults, neonates utilize a unique mode of nutrient absorption: macromolecules are absorbed in bulk and subsequently degraded by lysosomes. Our lab has identified three transcription factors crucial to this process: MAFB, cMAF, and BLIMP1. Deleting these genes from the intestinal epithelium prevents macromolecular uptake, leading to neonatal malnutrition and lasting growth defects. Further, our preliminary data indicate that the loss of these transcription factors restricts T cell infiltration in the neonatal intestine, and leads to lasting defects in T cell localization in adults. However, the mechanisms through which MAFB, cMAF, and BLIMP1 control neonatal nutrition and intestinal immune development remain poorly understood. The long-term goal of this project is to elucidate the mechanisms that direct neonatal nutrition and immunity, and determine the long-term functional consequences to organismal health. There is a pressing need to understand nutrition-immune connections mechanistically, as undernutrition currently affects over 140 million children globally and is implicated in almost half of pediatric mortality cases. To this end, the aims proposed in this application will provide a mechanistic understanding of the role of MAFB, cMAF, and BLIMP1 in the neonatal intestine. Aim 1 will leverage bioinformatic analysis combined with genetic mouse models to define the gene regulatory networks controlled by these transcription factors, and how these networks control the function of absorptive epithelial cells. Aim 2 will utilize loss-of-function mouse models to determine how MAFB, cMAF, and BLIMP1 regulate the infiltration of diverse immune populations in the neonatal and adult intestine, and how these transcription factors impact immune cell function and susceptibility to infection. The proposed research will take place under the mentorship of Dr. Terry Lechler within the Duke University School of Medicine. This environment will provide a network of collaborators and experts (both clinical and basic science) in the fields of cell biology, developmental biology, and gastroenterology, that will provide input and feedback as this project progresses. This project will also utilize multiple core facilities and shred resource centers available on campus, in order to accelerate the progress of the proposed aims. The training plan also includes attending scientific conferences annually to receive feedback from the broader field. Together, the proposed project will reveal the molecular networks that control neonatal nutrition and immune development. This work will provide mechanistic insight into a poorly understood yet critical stage of life, and will inform future studies into the effects of neonatal malnutrition on human patients.
