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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017837-05
Application #
8529396
Study Section
Special Emphasis Panel (ZAA1-BB (80))
Program Officer
Radaeva, Svetlana
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$371,402
Indirect Cost
$134,840
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Barnes, Mark A; Roychowdhury, Sanjoy; Nagy, Laura E (2014) Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1. Redox Biol 2:929-35
Bakhautdin, Bakytzhan; Das, Dola; Mandal, Palash et al. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J Hepatol 61:1029-37
Thapaliya, Samjhana; Runkana, Ashok; McMullen, Megan R et al. (2014) Alcohol-induced autophagy contributes to loss in skeletal muscle mass. Autophagy 10:677-90
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Roychowdhury, Sanjoy; Chiang, Dian J; McMullen, Megan R et al. (2014) Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1? Pharmacol Res Perspect 2:e00061
Cresci, Gail A; Bush, Katelyn; Nagy, Laura E (2014) Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res 38:1489-501
Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy et al. (2013) Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis. Hepatology 57:1980-91
Dixon, Laura J; Flask, Chris A; Papouchado, Bettina G et al. (2013) Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 8:e56100
Dixon, Laura J; Barnes, Mark; Tang, Hui et al. (2013) Kupffer cells in the liver. Compr Physiol 3:785-97
Roychowdhury, Sanjoy; McMullen, Megan R; Pisano, Sorana G et al. (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773-83

Showing the most recent 10 out of 14 publications