The application describes a 5-year training program for the development of an academic career in Alcohol and Lung Biology research for Dr. Viranuj Sueblinvong, Assistant Professor of Medicine on the tenure track at Emory University. With the support of this K08 Award, she will develop and refine her skills as a biomedical investigator and study the mechanisms by which chronic alcohol ingestion interferes with lung repair following an acute injury in an experimental mouse model. Dr. David Guidot, an internationally-recognized expert in the biology of the 'alcoholic lung', will mentor her scientific and career development. H has mentored many research trainees, including four faculty members supported by NIH K Awards and two by VA Career Development Awards. He is funded for his alcohol and lung research by the NIH and the VA, and collaborates with leading investigators in this field. In parallel, a mentoring committee comprised of senior investigators at Emory University has been formed to help mentor and guide Dr. Sueblinvong's scientific career development. Investigators in the Emory Alcohol and Lung Biology Center have shown that chronic alcohol ingestion is associated with an increased incidence of acute lung injury (ALI), and that this risk is likely driven by alcohol- induced oxidative stress. However, the effects of alcohol on repair and recovery processes following ALI have not been studied. Our preliminary data in a relevant pre-clinical animal model suggest that alcohol ingestion interferes with lung repair following bleomycin-induced ALI. We have novel evidence that this pathophysiological sequence begins with a dampening of signaling by Nrf2, the transcription factor required to activate the anti-oxidant response element (ARE). As a consequence, expression of the critical anti-oxidant thioredoxin-1 (Trx1) is dampened, further inhibiting activation of the ARE as one of the functions of Trx1 is to stabilize Nrf2. Consistent with this proposed sequence, either the activation of Nrf2 with sulforaphane (a naturally-occurring compound that has been shown to activate Nrf2) or the nuclear-specific over-expression of Trx1 would result in the attenuation of transforming growth factor-?1 (TGF?1) expression. These results lead us to hypothesize that alcohol disrupts the dynamic interactions between Nrf2 and Trx1 and that the consequent oxidative stress induces the aberrant expression of TGF?1 which impairs the ability of the lung to repair and recover from injury. The experimental approaches are designed to test this hypothesis, and these studies are expected to provide a scientific basis for the underlying mechanisms by which alcohol interferes with normal repair following ALI. This program of research, together with the collective expertise within Emory University and its focus on nurturing exceptional junior scientists, constitute an ideal setting for a physician-scientist at this critical stage of her carer development to acquire the diverse and specialized skills necessary to become an independent investigator focused on improving the health of individuals suffering from alcohol use disorders.

Public Health Relevance

Recent studies have identified previously unrecognized effects of chronic alcohol ingestion on the lung that can greatly increase the risk of severe lung injury and death even in otherwise healthy-appearing individuals. Experimental data discussed in this application provide novel evidence that chronic alcohol ingestion interferes with normal repair processes in the lung following injury. The proposed studies will investigate the mechanisms by which alcohol interferes with normal repair and can cause chronic lung damage and scarring.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AA021404-02
Application #
8541686
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Jung, Kathy
Project Start
2012-09-10
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$165,294
Indirect Cost
$12,244
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sueblinvong, Viranuj; Liangpunsakul, Suthat (2014) Relationship between serum leptin and chronic obstructive pulmonary disease in US adults: results from the third National Health and Nutrition Examination Survey. J Investig Med 62:934-7
Sueblinvong, Viranuj; Kerchberger, Vern E; Saghafi, Ramin et al. (2014) Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice. Alcohol Clin Exp Res 38:336-43
Sueblinvong, Viranuj; Tseng, Victor; Smith, Tierra et al. (2014) TGF?1 mediates alcohol-induced Nrf2 suppression in lung fibroblasts. Alcohol Clin Exp Res 38:2731-42
Sueblinvong, Viranuj; Neveu, Wendy A; Neujahr, David C et al. (2014) Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury. Adv Biosci Biotechnol 5:19-30