THE VANDERBILT UNIVERSITY
This request for an Administrative Supplement to the parent grant (5 R01 AA015752-03) entitled "Intracellular Therapeutics for Inflammatory Liver Injury" is responsive to NOT-OD-09-056 (NIH Announces the Availability of Recovery Act Funds for Administrative Supplements). Consistent with the intent of NIH to provide administrative supplements for the purpose of accelerating the tempo of scientific research on active grants, herein we propose to increase scientific personnel, and purchase additional materials and supplies to accelerate scientific discovery within the scope of our research on Alcoholic Liver Disease (ALD) which afflicts an estimated 2 million patients in the US with an astounding 65% mortality rate over a 4 year period. The requested additional personnel and supplies will allow us to accelerate the production and purification of a novel class of therapeutics to counteract alcohol-enhanced inflammation and apoptosis of the liver. The primary goals of the project remain unchanged, and are in support of our hypothesis that acute or chronic alcohol abuse alters homeostatic balance that exists between intracellular mediators and suppressors of proinflammatory signaling. This signaling culminates in genetic reprogramming of liver cells manifested by expression of proinflammatory and proapoptotic mediators. We have developed a cell-penetrating nuclear import inhibitory peptide as a prototype of a new class of anti-inflammatory and anti-apoptotic agents which suppresses production of proinflammatory cytokines/chemokines, prevents massive liver apoptosis I necrosis, and reduces mortality rates in animal models. We will advance our study on how ethanol alters the opposing roles of two key intracellular mediators (STAT1) and (STAT3) in T cell-mediated hepatitis model. We will expand our successful design and in vivo delivery of physiologic suppressors of cytokine signaling to the cytoplasmic protein known to ablate proinflammatory signaling in macrophages which play a significant role in alcohol-associated inflammatory liver injury. Cumulatively, these studies will advance our concept of intracellular protein therapy to extinquish alcohol-exacerbated liver inflammation and apoptosis.