Metabolic and inflammatory disorders such as metabolic syndrome, autoimmune and neurodegenerative diseases, are increasing at alarming rates, with little progress made in untangling their causal connection or mitigation of mortality. Emerging human multiorgan microphysiological systems (MPSs), in combination with multiomics and systems biology, offer new exciting possibilities to provide clarity in metabolic and inflammatory diseases through controlled interaction of multiple MPSs as well as components of the innate and adaptive immune system. MPSs are reductionist in vitro models, comprising multiple cell types, specialized microenvironments, and perfusion, that capture salient features of in vivo organ behavior. We are focused on identifying causation in gut-liver-brain immunometabolic pathologies and explore how disruption of tissue-immune homeostasis leads to the emergence of metabolic diseases. While this approach might yield tangible targets in disease prevention and treatment, it will also contribute to our understanding of humoral physiology of the gut-liver-brain axis, the role of innate and adaptive immune cells for tissue regeneration, and susceptibility of the axis to metabolic perturbation.
Projects
Role of MR1-Restricted Lymphocytes of the Gut-Liver Axis in Health and Disease
Recently discovered MR1-restricted lymphocytes, such as MAIT cells, represent a heterogeneous population of immune cells that, interestingly, have a unique ability to recognize a number of metabolites as their antigen. Previous studies have found a connection between their migration and proliferation and several autoimmune disorders, however their exact role in either prevention or potentiation of these diseases remains to be established. Given their high frequencies in mucosal as well as hepatic tissue, we are interested in the role they might play in concurrent pathologies such as IBD and autoimmune liver diseases, as well as the therapeutic potential of engineered MR1-restricted lymphocytes.
Identifying immunometabolic modulators of Gut-Liver-Cerebral homeostasis.
Despite well described connections between the gut, liver and brain, many mechanisms contributing to their humoral metabolic, immunological and structural homeostasis remain unidentified. Our preliminary data suggest that the behavior and maturation of individual organ systems greatly differs during their interaction as opposed to isolation primarily due to metabolic changes and tissue-immune interactions. Identifying critical factors responsible for these phenomena would open new venues for therapeutic interventions, regenerative medicine and tissue engineering.
Deciphering the role of lipid metabolism and gut-liver-cerebral interactions in mitochondrial neurodegenerative pathologies
Evidence of ferroptosis and mitochondrial disfunction playing a role in the death of dopaminergic neurons is mounting and increased interest exists in the connection between neuroinflammatory conditions, ferroptosis and fatty-acid metabolism. Our preliminary work implicates changes in neuronal lipid metabolism due to increased local inflammation and activation of microglia, to further modulate disease progression. Our established model of the gut-liver-cerebral axis offers the opportunity to chart causal relationships between systemic alteration of lipid metabolism, immunity and neurodegenerative disease.