Funding Opportunity Description

Research Objectives - Background

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites grant applications to study the cellular and molecular mechanisms of tissue injury caused by ethanol consumption. Virtually every system of the body is impacted by alcohol abuse, and the resulting pathological conditions contribute to increased mortality and morbidity among all groups and genders. The NIAAA is especially interested in comparative and interactive (or integrative) research that elucidates mechanisms of injury common to many body and organ systems, with the eventual goal of identifying early markers of ethanol induced pathology and developing therapeutic strategies to serve multiple alcohol-related disorders. Projects that bring together and integrate the work of investigators in diverse scientific disciplines are encouraged. Projects that foster collaborations between investigators in the clinical and basic sciences and/or focus on translational research are especially encouraged. Examples of scientific disciplines include microbiology, immunology (including innate and mucosal and neuro-immune interactions), biochemistry, pathology, systems biology, (proteomics, genomics, metabolomics and lipidomics etc.), molecular genetics, bioengineering, imaging technology, and mathematical modeling. Excessive alcohol intake often results in life-threatening medical disorders stemming from selective cell and tissue injury. Moreover, ethnic, gender and age differences in onset and severity of clinical pathology are observed. Although the underlying physiology and biochemistry of all cells is similar, manifestations of alcohol damage in adult and fetal tissue and organ systems may appear quite different, depending on the specificity and course of the disease following the alcohol insult. The initiating events at the molecular and cellular levels leading to alcoholic hepatitis, pancreatitis, immune system dysfunction, lung injury, cardiovascular compromise, neoplasia, bone disorders, brain tissue injury and peripheral neuropathy are not fully understood. However, evidence suggests that some common mechanisms may underlie tissue injury induction. For example, inflammatory mediators are involved in hepatitis, pancreatitis, and vascular disorders associated with alcohol abuse. Oxidant stress caused by alcohol metabolism is a common element in cellular injury in liver, pancreas, lung, and brain. Topics of interest may include enhancement of tissue injury by inflammatory mediators and their modifications; generation of reactive oxygen species during ethanol metabolism; induction of pro-apoptotic, anti-apoptotic or other pathways involved in ethanol toxicity. Other areas of interest include the horizontal transfer of active genetic elements through apoptotic bodies; and the differential expression of genes that participate in cell injury and regulate downstream signaling pathways. Systems biology approaches utilizing genomics, proteomics, metabolomics and mathematical modeling, that can identify changes in gene expression and protein modifications that trigger injury in multiple tissues are encouraged. The knowledge gained from this initiative will provide the foundation for identification of sentinel markers of tissue injury and the development of new therapeutics to control or modify outcomes of alcohol abuse. Areas of investigation under this PA could include, but are not limited to:

• Elucidation of the roles of ethanol and ethanol metabolites, coincident with other factors such as stress, infectious agents, nutritional supplements, iron, fat, antioxidant depletion, and regulatory peptides, inflammation, immune responses on the cell surface and molecular signaling cascades that lead to tissue injury.
• Elucidation of the role of vascular organ interface disruption and cell signal processing in the initiation of organ injury promoted by ethanol.
• Determination of the impact of ethanol on the cell membrane and molecular signals that instruct stem cells to replace damaged tissue
• Elucidation of the effects of ethanol on stem cell development and function.
• Evaluation of the mechanistic basis for adult, fetal, racial/ethnic and sex and gender-based differences in clinical manifestations of organ injury.
• Determination of the mechanisms by which free radicals and shifts in redox states during ethanol ingestion and metabolism contribute to cellular damage and the potential value of antioxidant therapy
• Evaluation of interactions between gene regulatory elements and factors that control developmental, tissue-specific, and temporal expression of alcohol metabolizing enzymes in all organs through development and aging.
• Identification of genes and genotypes that confer susceptibility and/ or resistance to ethanol-induced cell/tissue damage.
• Elucidation of the initiation, progression, and maintenance processes in tissue injury using targeted mutations
• Development of non-invasive biomarkers for the early detection of alcohol induced tissue injuries using new technologies involving organ, molecular and cellular imaging, immunomics, metabolomics, proteomics and lipidomics.
• Determination of the relative roles of ethanol and ethanol-induced toxic substances in initiating tissue damage in the brain and nervous systems of multiple organs (i.e. peripheral neuropathies)
• Investigation of neuro-immune dysfunction in ethanol/stress induced tissue damage
• Role of ethanol-induced excitotoxicity during withdrawal on organic brain damage

Prepared:  March 9, 2006