PA-20-183 NIH Research Project Grant (Parent R01 Clinical Trial Required)
PA-20-184 NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
PA-20-185 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-194 NIH Exploratory/Developmental Research Grant (Parent R21 Clinical Trial Required)
PA-20-195 NIH Exploratory/Developmental Research Grant (Parent R21 Clinical Trial Not Allowed)
PA-20-196 NIH Exploratory/Developmental Research Grant (Parent R21 Basic Experimental Studies with Humans Required)
PA-20-200 NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
PAR-21-038 - Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed)
PAR-21-039 - Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Basic Experimental Studies with Humans Required)
The purpose of this Notice is to inform potential applicants of the NIAAA’s special interest in research project applications studying the harmful effects of alcohol on the body’s tissues, organs, and systems in diverse populations across the lifespan.
Background
Alcohol consumption is among the 10 leading causes of disability-adjusted life years and ranks as the third leading preventable cause of death. In the United States alone, the cost of excessive alcohol use reached $249 billion/year, of which nearly 20 percent is for direct medical expenses. The harmful use of alcohol affects virtually all tissues and is linked with dysfunction and failure of many organs and systems including the liver, heart, pancreas, lung, bone, and skeletal muscle, as well as digestive, vascular, endocrine, and immune systems. Excessive and chronic alcohol consumption increases the risk of several infectious diseases and cancers and can cause birth defects, resulting in major public health concerns. Besides, alcohol misuse often results in comorbidity and complex pathologies, further increasing the healthcare burden.
Within each organ system, there is a spectrum of possible alcohol-related pathological processes reflected by specific manifestations. For example, the liver may exhibit fatty liver, alcoholic hepatitis (AH), or cirrhosis. In the lung, alcohol consumption is associated with acute respiratory distress syndrome and an increased risk of pneumonia. Alcohol-related organ diseases (AROD) often exhibit highly heterogeneous, multifactorial pathologies with a long preclinical period prior to the onset of clinically significant symptoms. Studies have shown that various environmental and host factors such as genetics, nutrition, co-existing diseases, age, gender, and race/ethnicity may be involved in the incidence and severity of AROD. Moreover, people with one alcohol-related disease are at increased risk for multi-organ damage, implicating systemic response to alcohol. For example, in severe AH, sepsis and multi-organ failure are often observed. However, it is still unknown why some people who drink heavily but not others develop the disease, and the underlying mechanisms on the development and progression of alcohol-related diseases have not been fully understood.
Emerging evidence indicates that alcohol-induced injuries develop in a cascade manner and reflect complex interactions between various endogenous and exogenous factors. Many alcohol-related diseases are associated with differential expression of genes that inhibit tissue repair and promote inflammation. Sustained, and a high level of inflammation and endotoxemia are the key players in tissue damage that, in combination with suppressed wound healing, lead to the failure of tissue repair, resulting in the progression of acute injury to chronicity. Other mechanisms that contribute to the initiation and progression of alcohol-related tissue injury include abnormal lipid metabolism, oxidative stress, and the production of reactive oxygen species as well as remodeling of the extracellular matrix and fibrogenesis. A better understanding of various molecular and cellular mechanisms of alcohol-induced tissue injury and organ damage, both at the systemic and local levels, will provide new avenues for developing effective treatments of AROD.
Research Objectives
Applications submitted to this NOSI are expected to elucidate the complex biology of alcohol-induced pathology and address any areas where knowledge gaps exist. Research on understanding and managing AROD is still needed. To address these needs, research approaches must be conducted ranging from the fundamental mechanisms to clinical studies that analyze existing, or newly collected, data and biological specimens using novel analytical tools. Basic research programs that integrate host and environmental factors with clinical aspects and identify mechanisms or processes related to clinically relevant pathological conditions, and/or translational studies that are potentially interventional and that identify therapeutic targets for the treatment of AROD are of particular interest.
Areas of interest and examples of research studies responsive to this NOSI include but are not limited to those listed below.
Pathophysiology of AROD
- elucidate the complex, inter-related pathophysiologic processes associated with initiation and subsequent progression of tissue injury by alcohol. Studies focused on this aspect include, but are not limited to, any of the following:
- Alcohol metabolism, the interaction of alcohol and its metabolites with signaling pathways, and their roles in alcohol-induced tissue damage
- Mitochondrial dysfunction
- Endothelial and epithelial injury
- Alterations in redox potentials
- Abnormalities in circadian-regulated gene expression
- Mechanisms underlying phenotypic changes in cellular components during different phases of the disease
- Alcohol-mediated, various forms of cell death
- Alcohol-induced DNA damages and epigenetic modifications
- Fibrogenesis
- identify the most rudimentary cause of the end-organ disease at a molecular, cellular, and genomic level that can then be advanced into translational and clinical projects
- identify the host and environmental risk factors that predispose or trigger AROD
- study gender differences in clinical manifestations of organ damage by alcohol
- develop humanized immune system (HIS) mouse (or other animal) models, particularly models that do not need to use fetal sources of human cells, or establish organoid systems to provide suitable models of tissue injury resulting from alcohol use that reflects human clinical situations
- identify mechanisms responsible for acute vs chronic organ dysfunction associated with alcohol
- study the effects of alcohol on the role of stem/progenitor cells in tissue regeneration and repair of the liver, pancreas, and other organs.
- investigate mechanisms controlling cell fate decisions and self-renewal after alcohol-induced injury and the potential for cell plasticity of resident progenitor cells in the presence of alcohol
- investigate alcohol’s effect on various tissues at different stages of development, including in utero at all stages of gestation
- compare human tissue samples to validate and determine the relative contribution of different mechanisms of tissue injury and repair uncovered in distinct animal models
- develop bioinformatics, computational, and mathematical modeling to integrate experimental and clinical information and systems biology of clinically relevant alcohol-induced tissue injury
Microbiome
- identify specific bacterial strains, fungi, microbial metabolites and elucidate the mechanisms of bacterial/fungal dysbiosis that contribute to AROD
- study alcohol-induced host-microbiome interactions (activation pathways and molecules) that contribute to differences in clinical phenotypes and disease courses
- study impacts of the microbiome and pre/probiotic interventions on immune function, inflammation, and the potential effect on therapy
- investigate the mechanisms of alcohol-associated malnutrition and increased intestinal permeability
Immunity and inflammation
- investigate the mechanisms responsible for the activation of local immune and inflammatory responses in alcohol-related tissue injury
- study alcohol’s effects on maturation and development of immune cells from precursors
- study the role of local versus systemic inflammatory changes in alcohol-related disease processes
- study alcohol’s effects on the progression of and complications from viral-related diseases
- study alcohol’s effects on innate and adaptive immunity, and their association with various organ damage
- study immunological changes in alcohol-damaged organs and systems that contribute to impaired tissue wound healing as well as response to infections
- study how inflammation alters the organ’s microenvironment, including stem cell niche, to promote pathological tissue remodeling and neoplastic transformation
- study how alcohol-induced dysregulation of the immune system drives acute inflammation to the chronic stage, or hyperinflammatory responses known as cytokine storm
- investigate alcohol-induced damage-associated molecular pattern molecules (DAMPs) and pathogen-associated molecular pattern molecules (PAMPs) and their roles in AROD
Organ-organ interactions
- identify common and unique aspects of alcohol-induced pathology at multiple organ sites
- study how alcohol interferes with exosome biogenesis and function to promote cell-cell communication and the role of alcohol-induced exosome in the initiation of early pathogenesis
- develop exosome-based liquid biopsies to monitor the progression of various AROD
- identify the pathological mechanisms and consequences including gut-liver, gut-lung, gut-brain, liver-kidney, and other axes that are mediated by alcohol misuse
- study how alcohol modifies the interactions between neural, endocrine, and immune systems
Comorbidity
- study how harmful alcohol use affects the clinical progression of the primary diseases including diabetes, cardiovascular diseases, lung diseases, and other organ diseases
- study how harmful alcohol use impacts the effectiveness of the medicinal therapy and immediate and long-term prognosis of existing diseases including infectious diseases
Health disparities
- employ mechanistic, hypothesis-driven studies to identify biological factors and pathways contributing to AROD pathobiology among racial/ethnic populations.
- employ big data technology, systems biology, and simulation modeling to address health disparities in AROD
- identify risk factors, genetics, and biological markers for AROD in the context of ethnic, socioeconomic, and other diverse populational factors
- examine underlying biological factors and mechanisms responsible for the onset, progression, and outcome of AROD in racial/ethnic minorities, as well as socioeconomic and other diverse populations
Application and Submission Information
This notice applies to due dates on or after February 5, 2021 and subsequent receipt dates through May 8, 2023.
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.
- PA-20-183 NIH Research Project Grant (Parent R01 Clinical Trial Required)
- PA-20-184 NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
- PA-20-185 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
- PA-20-194 NIH Exploratory/Developmental Research Grant (Parent R21 Clinical Trial Required)
- PA-20-195 NIH Exploratory/Developmental Research Grant (Parent R21 Clinical Trial Not Allowed)
- PA-20-196 NIH Exploratory/Developmental Research Grant (Parent R21 Basic Experimental Studies with Humans Required)
- PA-20-200 NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
- PAR-21-038 - Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed)
- PAR-21-039 - Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Basic Experimental Studies with Humans Required)
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
- For funding consideration, applicants must include NOT-AA-20-024 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.
Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:
Scientific/Research Contact(s)
Li Lin
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-827-7749
Email: linli@mail.nih.gov
Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Financial/Grants Management Contact(s)
Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-443-4704
Email: jfox@mail.nih.gov
