Effect of PPARy Ligands on Alcohol-Induced Alveolar Macrophage Oxidative Stress

Summary

Principal Investigator: Samantha M Yeligar
Abstract: DESCRIPTION (provided by applicant): Chronic alcohol abuse increases patients'risk of developing Acute Respiratory Distress Syndrome (ARDS) and respiratory infections. In alveolar macrophages (AMs), NADPH oxidase (Nox) 1, Nox2, and Nox4 are critical sources of reactive oxygen species (ROS), and Nox2 is essential for the respiratory burst involved in killing microbes after phagocytosis. However, excessive ROS production suppresses phagocytosis. Chronic alcohol ingestion increases Nox enzyme levels, leading to AM oxidative stress and dysfunction. These alcohol-induced derangements can be reversed by treatment with peroxisome proliferator-activated receptor gamma (PPAR?) ligands, such as pioglitazone and rosiglitazone. In these studies, the PI will elucidate the molecular mechanisms that modulate alcohol-induced AM Nox expression and activity by studying microRNAs (miRs): Nox1-related miR-1264, Nox2-related miR-107, and Nox4-related miRs-363 and -92a/b (Aim 1). Then, the PI will examine how PPAR? ligands attenuate these miRs to reverse alcohol-mediated AM Nox1, Nox2, and Nox4 expression, oxidative stress and compromised phagocytosis (Aim 2). These hypotheses will be investigated by using a mouse model of chronic alcohol consumption, an in vitro ethanol exposed mouse AM cell line, MH-S, and AMs isolated from human subjects. The objective of the studies outlined in this application is to demonstrate that targeting PPAR? constitutes a novel therapeutic approach to ameliorate alcohol-induced AM dysfunction. If successful, these investigations could have considerable translational impact on the management of patients with a history of alcohol abuse by setting the stage for future clinical studies. The PI's focus in alcohol research began during her pre-doctoral dissertation project investigating the detrimental effects of chronic alcohol abuse in the liver, focusing on mechanisms underlying the participation of ROS and inflammatory mediators that alter liver endothelial cell and macrophage function. During post- doctoral training in the laboratories of Drs. Brown and Hart, she acquired additional expertise with numerous molecular biology techniques and with animal models of chronic alcohol ingestion. During the K99 mentored phase of the proposed project, the applicant will further expand her repertoire of skills by receiving hands-on training in: a) techniques to perform and characterize Klebsiella pneumonia bacterial challenges in the airways of mouse models to assess alveolar macrophage phagocytosis in vivo, b) methods to directly deliver PPAR? ligand therapeutics to the lungs of mouse models using intranasal administration, and c) skills required to develop and manage colonies of knockout and transgenic mice. These skills will be acquired through the execution of the proposed studies with the assistance and training of the mentors'labs during the first two years of the proposed project period. The focus of these studies will permit a natural extension of the candidate's interest in the regulation of miRs in the context of chronic alcohol ingestion. t is anticipated that her additional expertise in this area will naturally promote her growing independence from her mentors into the R00 independent phase. During the proposed award, in addition to didactic courses in current molecular biology techniques and biostatistical methods, the PI will gain non-laboratory skills important for her career development as an independent research investigator by participating in seminars and activities related to the responsible conduct of research, laboratory management, and faculty career development. Support from this K99/R00 grant will provide the PI an outstanding opportunity to expand and consolidate her experimental and laboratory skills and support her career goal to become an independent investigator and obtain a faculty position at an academic institution. The likelihood that she will achieve these goals is supported by planned mentorship from well-established investigators, the abundant scientific opportunities within the Emory University Alcohol and Lung Biology Center, and a hypothesis-driven application exploring novel mechanisms of an important and clinically relevant pathophysiological disorder. The proposed program will permit the PI to build her publication record, collect critical preliminary data for subsequent grant applications, present research findings at national meetings, and gain experience in manuscript writing and grant preparation. Thus, this K99/R00 application provides an excellent opportunity to advance the career of a talented and promising investigator.
Funding Period: 2013-09-01 - 2015-08-31
more information: NIH RePORT

Research Grants

  1. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
  2. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
  3. Zinc deficiency in the alcoholic lung
    Pratibha C Joshi; Fiscal Year: 2013
  4. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
  5. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  6. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
  7. Mechanisms regulating autophagy in alcohol-induced liver injury
    Wen Xing Ding; Fiscal Year: 2013
  8. Center for Novel Therapeutics for HIV-Associated Cognitive Disorders
    Justin C McArthur; Fiscal Year: 2013
  9. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
  10. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
    ..Thus, the DEARC will serve as a nexus of alcohol research in Central New York and as a beacon for national activities. ..
  2. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  3. Zinc deficiency in the alcoholic lung
    Pratibha C Joshi; Fiscal Year: 2013
    ....
  4. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  5. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  6. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
    ..The projects are highly interactive, and all three take full advantage of the proposed cores. ..
  7. Mechanisms regulating autophagy in alcohol-induced liver injury
    Wen Xing Ding; Fiscal Year: 2013
    ..Ultimately, such knowledge has the potential of offering novel therapeutic approaches for treating alcoholic liver pathogenesis by modulating autophagy. ..
  8. Center for Novel Therapeutics for HIV-Associated Cognitive Disorders
    Justin C McArthur; Fiscal Year: 2013
    ..5. To identify and validate surrogate biomarkers based on proteomics and lipomics. ..
  9. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  10. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
    ..We are optimistic that our research efforts will contribute to reductions in the incidence of, and morbidity and mortality from, this devastating disease by translating basic research into clinical practice. ..
  11. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  12. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  13. PPAR gamma and Nox4 in pulmonary hypertension
    Roy L Sutliff; Fiscal Year: 2013
    ..The long-term goals of this proposal are to define mechanisms by which PPARg activation attenuates PH and to facilitate the development of new PH therapy. ..
  14. Emory Alcohol and Lung Biology Center
    DAVID MARSHALL GUIDOT; Fiscal Year: 2013
    ..abstract_text> ..
  15. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  16. Alcohol abuse, oxidative stress, and zinc deficiency in lung disease
    Ashish J Mehta; Fiscal Year: 2013
    ....
  17. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  18. Functional characters of non-coding RNAs in alcoholic liver injury
    Fanyin Meng; Fiscal Year: 2013
    ..abstract_text> ..
  19. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..
  20. Novel molecular and cellular approaches for alcoholism medication development
    Robert A Harris; Fiscal Year: 2013
    ..The PPG has both internal and external advisory board members, providing expert guidance from scientists with a wide range of expertise in drug development and therapeutics. ..
  21. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  22. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  23. Peroxisome Proliferator-Activated Receptor (gamma) in Lung Cancer
    Raphael A Nemenoff; Fiscal Year: 2013
    ....