Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY (See instructions): Metabolism is the core process underlying essentially all biological functions. The application of this concept to the immune system, known as immunometabolism, is arguably one of the most active and transformative research topics in immunology. The critical link between metabolism and immunity is highlighted by the findings that immunometabolism shapes dendritic cell (DC) function, T cell responses and adaptive immunity, and contributes to cancer progression and therapy. However, molecular mechanisms linking the metabolic state of immune cells with in vivo immune responses remain largely unclear, and integrative, systems-level understanding and therapeutic targeting of immunometabolism are lacking. My laboratory studies the interplay between metabolism and immunity, and how understanding immunometabolism reveals new biology and disease targets. The long-term goals of my research program are to establish the metabolic and signaling programs that direct DC- and T cell-mediated adaptive immune responses. We approach these questions by multidisciplinary strategies, ranging from immunology, genetics, cell biology and biochemistry, to in vivo models of cancer and inflammation. The central hypothesis that guides our research is that metabolic pathways are inextricably connected to immune cell state and fate and adaptive immune responses, and by understanding these connections, we gain new concepts and disease targets. This hypothesis leads us to address the following three key questions in immunometabolism. First, we will establish immunometabolic control of DC subsets and adaptive immunity via mitochondrial and lipid pathways. Second, we will use functional genomics approaches to systemically explore metabolic control of DC subsets and function. Third, we will determine the roles of nutrients in mediating intercellular communication between DCs and T cells or tumor cells. Completion of these aims are expected to identify novel mechanisms of intracellular and intercellular metabolic checkpoints underlying DC subsets, T cell responses and adaptive immunity. Our established contributions in the field of immunometabolism, expertise in the studies of both DCs and T cells, and experience in the synthesis of hypothesis-driven and systems-level approaches, make us uniquely positioned to produce fundamental discoveries in immunometabolism and new strategies for translation.
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