Alcohol consumption can be characterized as a chronic environmental stress to the organism. Alcohol exposure results in complex cellular and organismal adaptations to respond to and manage this insult. In most individuals, modest alcohol consumption over a life-time does not result in substantive health risks, and in some systems, may actually be protective. Yet, in other individuals, or with more substantive consumption, chronic alcohol abuse increases risk for disease, including alcoholic liver disease (ALD), one of the most clinically important diseases resulting from chronic alcohol abuse. What marks the transition from a benign or even protective effect of ethanol to the transition to a pathophysiological development of ALD? Understanding the genetic, molecular, cellular and physiological responses to ethanol that """"""""tip the balance"""""""" from an adaptive response to a maladaptive/ pathological response is critical to the development of therapeutic strategies to prevent and/or reverse ALD. In this proposal for an exploratory/developmental alcohol research center, we plan to leverage the many strengths of the world-class research community at the Cleveland Clinic and Case Western Reserve University to establish an interdisciplinary team of investigators expert in measuring in vivo markers of biochemical and molecular stress, as well as assessing the cellular/organismal responses to that stress. Basic scientists and clinical investigators will interact not only to translate basic science advances to clinical investigations (bench to bedside), but also to translate the clinical experience into refining and advancing the approach of basic research studies (bedside to bench) on the mechanisms for ALD. The Center will focus on four thematic areas of investigation to understand the mechanisms for ALD: 1) Measuring biochemical and molecular markers of ethanol-induced stress, 2) Assessing cellular responses to ethanol-induced stress, 3) Understanding the integrative organismal adaptations to ethanol and 4) Translating advances from the laboratory to human clinical experiments. Exploratory/Pilot projects in each of the thematic areas will allow for the exploration of novel areas of investigation that exploit the interdisciplinary expertise of Center members. The Administrative Core will facilitate these interdisciplinary interactions via organization of interactive meetings, including bi-monthly meetings of the Center membership, invited seminar speakers and an annual retreat. The Animal Models and Cell Isolation Core, as well as a Clinical Core, will allow for synergistic advances in basic and clinical investigations by providing biological and clinical samples to Center members to test specific hypotheses. Our long-term goal is to promote interdisciplinary investigations into understanding the molecular targets of ethanol-induced damage, as well as the cellular and systemic responses to damage, in order to rationally design and test therapeutic interventions to either slow and/or reverse the progression of ALD.
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