Over-Expression of microRNA-126 in Macrophages for Treatment of Atherosclerosis

Summary

Principal Investigator: Suzette Laing
Abstract: DESCRIPTION (provided by applicant): Periodontal infection has been shown to increase the incidence and severity of atherosclerosis, which is now the number one cause of morbidity and mortality in the United States. Furthermore there is increasing evidence linking obesity, which is a major risk factor of atherosclerosis, to periodontal disease. In atherosclerosis, the earliest lesions contain macrophages that have phagocytized and accumulated modified lipoproteins. The continued monocyte recruitment and cholesterol accumulation in the vessel wall facilitates chronic disease progression. The identification of several subsets of microRNAs involved in vascular repair and homeostasis have made them an attractive target for atherosclerosis research. Recent studies have identified miR-126 as an essential mediator of vascular integrity and angiogenesis through its regulation of vascular endothelial growth factor 1 signaling, and modulation of vascular adhesion proteins to control leukocyte traffic across the vessel wall. In atherosclerosis related pathology, it was shown to reduce the size of the vascular lesions by activation of the CXCL12/CXCR4 axis to mobilize and incorporate endothelial progenitor cells at the site of injury. Since macrophages derived from bone marrow hematopoietic stem cells (HSC), are key to the initiation and progression of atherosclerosis, the therapeutic potential of over-expressing beneficial genes and/or knocking-down detrimental genes in macrophages, or using the macrophage as a delivery mechanism is gaining attention in the gene therapy field. Our hypothesis is that over-expression of miR-126 in macrophages will mediate atheroprotection by reducing atherosclerosis plaque formation and increasing plaque stability. Through the use of our synthetic macrophage promote, our lab has previously been able utilize the macrophage as a delivery mechanism for Liver X receptor alpha and Brain-derived neurotrophic factor in atherosclerosis and neurodegeneration studies respectively. The goal of this study is to determine 1) if macrophages can successful deliver miR-126 to the vascular endothelium, 2) If delivery of miR-126 to the vessel wall protects the endothelium thereby decreasing atherosclerotic lesions and 3) if this protection/decrease in lesion is mediated by the CXCL12/CXCR4 axis. Answering these questions will be important for advancing the use of vascular gene therapy in a clinical setting and uncovering alternative approaches to vascular regeneration and remodeling. This research proposal supports training necessary for the applicant's career goal to become a dentist-scientist studying translational research in regenerative dentistry.
Funding Period: 2013-07-01 - 2016-06-30
more information: NIH RePORT

Research Grants

  1. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  2. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
  3. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
  4. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
  5. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
  6. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
  7. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
  8. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  9. Regulation of CNS viral persistence
    Cornelia Bergmann; Fiscal Year: 2013
  10. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013

Detail Information

Research Grants31

  1. 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. ..
  2. 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. ..
  3. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..
  4. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  5. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
  6. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  7. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  8. 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. ..
  9. Regulation of CNS viral persistence
    Cornelia Bergmann; Fiscal Year: 2013
    ..Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response...
  10. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013
    ..The 4DB Center will also serve to disseminate information, education, and training to a new generation of cancer physicists;a generation that will implement the power of physics to conquer the problems of cancer. ..
  11. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  12. Center of Research on Obesity and Cardiovascular Diseases
    Lisa A Cassis; Fiscal Year: 2013
    ....
  13. 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. ..
  14. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  15. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  16. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease. ..
  17. 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. ..
  18. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  19. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  20. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    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) ..
  21. Infarct Repair with Mesenchymal Stem Cell Subpopulation
    Buddhadeb Dawn; Fiscal Year: 2013
    ....
  22. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..
  23. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..