The NIH Mentored Research Scientist Development Award (K01) aims to ensure that a diverse pool of trained scientists is available to address nation's biomedical needs. This K01 Mentored Research Scientist Development Award application from a promising T-32 and F-32 funded early career investigator will provide support for an intensive, supervised career development experience through mentored research in preparation for transition to an academic research faculty position. The mentored research career development plan will focus on understanding the mechanisms of alcohol-mediated disruption of mesenteric lymphatic transport, lymphatic leakage, and the consequent alterations in perilymphatic adipose tissue (PLAT) functional phenotype. Specifically, the focus will be on how alcohol disrupts lymphatic integrity leading to lymphatic leakage of imunne cells into PLAT and the role of the PLAT immune cells on the development of IR, which is a new area of research to the candidate. Key elements of the candidate's research career development plan are: (1) to develop a research focus on the interaction between lymphatic immune cell leakage and PLAT immune cell role on insulin signaling and glucose uptake; (2) to establish how lymphatic leakage disrupts the immune dialog between intestinal mucosa and mesenteric lymph nodes; and (3) to develop expertise in alcohol- mediated immunometabolic consequences, particularly insulin resistance. The studies will focus on alcohol- induced lymphatic leakage via disruption of lymphatic endothelial tight junctions leading to PLAT IR and interrupting the immune dialog between intestinal mucosa and mesenteric lymph node.
Three specific aims will test the predictions that a) alcohol induces lymphatic leakage via disruption of lymphatic endothelial tight junctions; b) alcohol-induced lymphatic leakage of immune cells into PLAT leads to increased fTregs expansion disrupting the immune dialog between gut and mesenteric lymph nodes (MLN); c) PLAT fTregs are responsible for PLAT IR. The proposed studies will combine in vivo with in vitro approaches to critically test the hypothesis. The successful completion of these studies will provide new insights, into the pathological mechanisms of alcohol-induced insulin resistance and will bring a novel approach that will link lymphatic function and PLAT with alcohol immunomodulation leading to insulin resistance. The scientific environment at Louisiana State University includes a NIAAA-funded Comprehensive Alcohol Research Center and outstanding facilities for the candidate's research. Along with an excellent mentor, this environment will ensure the accomplishments of the proposed studies and the successful transition of the candidate to an academic research faculty position.
The proposed training plan will focus on the investigation of novel mechanisms involved in the development of adipose metabolic impairments and insulin resistance resulting from chronic alcohol. Specifically, studies will investigate how chronic alcohol disrupts visceral adipose immunity, in response to lymphatic vessel leakage. Combined, training in a new field of research, the mentoring, and the institutional environment will facilitate the applicant's successful transition to an independent research scientist.
