Specialized lipid mediators and mechanisms of resolution in vascular injury


Principal Investigator: Michael S Conte
Abstract: DESCRIPTION (provided by applicant): Failure of vascular interventions such as angioplasty, stenting, and bypass surgery remains a common clinical problem resulting in considerable morbidity, mortality, and healthcare expenditures. The most common cause of these failures is a narrowing of the vessel lumen ("restenosis") resulting from excessive thickening of the vessel wall (intimal hyperplasia) and scarring (fibrosis). The response of blood vessels to injury is initiated and potentiated by inflammation. The magnitude of this response, including its temporal and spatial extent, is a primary determinant of the vessel remodeling outcome. Recent studies have suggested that the resolution of inflammation is an active, rather than a passive process, and is mediated by specialized pro-resolving lipid mediators derived from polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These mediators - termed lipoxins, resolvins, protectins, and maresins - exert potent effects on inflammatory cells to turn off inflammation and promote a return of homeostasis. Recently we and others have identified direct actions of these pro-resolving mediators on vascular cells which suggest they may be important modulators of vascular healing, and candidate therapeutics for vascular disease. In this translational research proposal, we will examine the hypothesis that restenosis is caused by a relative deficit in resolution following vascular injury. We will examine the molecular mechanisms by which one important class of pro-resolving lipid mediators, the D-series resolvins, exerts anti-inflammatory and cytostatic effects on vascular smooth muscle (VSMC) and adventitial cells. We will characterize the endogenous resolution pathways that are operative in the setting of acute arterial injury using an established animal model, and their manipulation by either dietary or local drug delivery interventions. These studies will yield novel insights into the control of vascular healing, and may lead to new therapeutic approaches leveraging the unique pharmacobiology of pro-resolving lipid mediators in cardiovascular diseases.
Funding Period: 2013-08-21 - 2017-05-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  2. Leukadherins as novel compounds for treating restenosis
    ..This will pave the way for the future discovery of novel therapeutic agents to treat restenosis after PCI as well as other vascular inflammatory diseases. ..
  3. 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. ..
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..
  6. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  7. PAI-1 and Vitronectin in Failure of Coronary Revascularization
    William P Fay; Fiscal Year: 2013
    ..This application will study the roles of plasminogen activator inhibitor-1 and vitronectin in the failure of percutaneous coronary interventions. ..
  8. Improved Adventitial Rapamycin Therapy for Peripheral Artery Restenosis
    KIRK SEWARD; Fiscal Year: 2013
    ..If these Phase 2 studies are successful, we intend to move into pivotal clinical trials and ultimately seek FDA approval for a novel combination product. ..
  9. Targeting epithelial cells to treat pulmonary fibrosis
    Dean Sheppard; Fiscal Year: 2013
    ..abstract_text> ..
  10. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  11. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  12. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  14. Exercise, Diabetes, &Coronary Smooth Muscle Ca2+
    Michael Sturek; Fiscal Year: 2013
    ..Drugs currently approved for humans are very likely to find new uses in treatment of coronary disease. We are uniquely positioned to benefit the prevention and regression of coronary disease, which will improve health in the U.S. ..
  15. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  16. Cell Instructive Materials For Engineering Vascular Grafts
    Robert E Akins; Fiscal Year: 2013
  17. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  18. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  19. Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology
    CHARLES NICHOLAS SERHAN; Fiscal Year: 2013
    ..Selected synthetic SPM will be scaled-up for demonstration of their unique mode of action in vivo in a resolution pharmacology core using experimental disease models. Our broad goal is to bring forth new treatments in resolution. ..
  20. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  21. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  22. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  23. 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. ..
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  25. Carbon monoxide mediated inhibition of intimal hyperplasia
    Edith Tzeng; Fiscal Year: 2013