Browsing by Author "Karpac, Jason"

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Diet-NFkB interactions in the transcriptional regulation of metabolic homeostasis
Molecular And Cellular Medicine; TAMHSC; https://hdl.handle.net/20.500.14641/388; DHHS-NIH-National Institute of Diabetes and Digestive and Kidney Disorders
Project Summary/Abstract: Metabolic and innate immune responses, two primitive systems critical for the long-term homeostasis of multi- cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges. Unfortunately, as humans appear evolutionarily unprepared for modern diets, over-nutrition and dietary imbalances often leads to mis-regulation of these responses and the development of metabolic dysfunction. Uncovering the integration of these ancestral metabolic and innate immune systems thus advances both understanding of basic physiology and the complex etiology associated with metabolic disease. An over- arching goal of the research proposed here is to establish a framework of innate immune-metabolic signaling networks employing invertebrate models. Utilizing Drosophila, a powerful integrative physiology model, new insights derived from previous studies have revealed a role for the innate immune transcription factor NF-kB in modulating metabolic target gene expression during adaptation to dietary changes. NF-kB transcription factors, evolutionarily conserved regulators of innate immunity, are emerging as a critical node in the bidirectional communication and coordination of metabolic and innate immune signaling pathway interactions. It was uncovered that NF-kB antagonism of Foxo function (a key nutrient-responsive transcription factor) is crucial to influence metabolic target genes in diverse cell types to shape distinctive aspects of lipid metabolism (largely linked to catabolism - usage, breakdown, and mobilization). This antagonism subsequently balances energy homeostasis with diet-dependent nutrient supply and promotes metabolic adaptation. These findings highlight a critical need to explore the distinct molecular and cellular mechanisms, governed by ancient innate immune signaling pathways, that may shape the equilibrium between normal physiology and pathology associated with diet-mediated disruptions in lipid metabolism. To this end, it is possible that diet- and NF-kB-dependent antagonism of metabolic transcription factor function may be central to the integration of innate immune- metabolic signaling networks. Drosophila provide an invaluable, genetically tractable model to characterize such mechanisms; as these signaling networks are conserved from insects to humans, and many ancestral insect tissues combine functions of nutrient and pathogen sensing organs, highlighting the inherent association between metabolic state and innate immune function. There are three specific aims to this proposal: (i) to explore interactions between NF-kB and histone deacetylases in the control of diet-dependent chromatin remodeling and lipid metabolism, (ii) to determine whether unique signaling mechanisms direct diet- and NF-kB-dependent transcriptional attenuation (vs activation) of metabolic target genes, and (ii) to characterize NF-kB-modulated gene regulatory networks shaped by dietary imbalances and chromatin remodeling. Exploiting Drosophila to explore the origin of innate immune-metabolic interactions holds promise for an enhanced rate of uncovering novel mechanisms that underly lipid-metabolic imbalances and metabolic dysfunction.
NFkb: Integrator of Host-Diet-Microbiota Interactions
Molecular And Cellular Medicine; TAMHSC; https://hdl.handle.net/20.500.14641/388; DHHS-NIH-National Institute of Diabetes and Digestive and Kidney Disorders
Project Summary: Nutrition and dietary adaptation shape all aspects of animal physiology across taxa, including the composition and maintenance of intestinal microbiota, which, in turn, influence host animal metabolic responses. The reciprocal interactions between diet, host signaling networks, and microbiota define a physiological rheostat that governs host metabolism. Importantly, when these interactions are misregulated, the result is often metabolic dysfunction and disease. Thus, there is a critical need to explore the distinct cellular and molecular host signaling mechanisms that promote diet-microbe interactions and influence host physiology. The overall goal in this proposal is to investigate diet-dependent host signaling mechanisms, driven by the evolutionarily conserved, innate immune signaling pathway transcription factor NFkB, that influence intestinal microbiota homeostasis. I provide evidence that NFkB transcription factor function in the Drosophila intestine can govern microbiota maintenance and metabolic signaling pathway activity in response to specific changes in dietary macronutrients, putatively influencing microbiota-regulated aspects of host health and dietary adaptation. More specifically, I find that, in response to high carbohydrate / low protein dietary macronutrient ratios, NFkB activity can modulate the function of the 4EBP/TOR signaling pathway, a conserved regulator of physiology that couples nutrition, cellular energy homeostasis and mRNA translation. I hypothesize that intestinal NFkB function is required to maintain microbiota homeostasis in response to dietary changes through influencing host 4EBP/TOR signaling pathways. To address this hypothesis, I aim to utilize the fruit fly model, Drosophila melanogaster, to; (i) assess NFkB/4EBP/TOR integration by characterizing the cellular interactions of these signaling pathways and their impact on microbiota maintenance during dietary adaptation. A result of disruption of these signaling interactions is a significant change in mRNA translation within the intestine, thus I also plan to; (ii) explore the influence of intestinal translational on microbiota maintenance. Lastly, I anticipate that the changes I see in microbiota composition during dietary adaptation are impacting host physiology. Specifically, based upon current literature, I aim to; (iii) investigate the effect of NFkB-and- diet-dependent changes in microbiota maintenance on host proteolytic activity and amino acid homeostasis. Exploiting Drosophila to explore evolutionarily conserved host signaling mechanisms involved in maintaining commensal microbes under changing dietary conditions holds promise for developing integrative diet- microbiota interaction frameworks that are useful for optimizing human health.