MicroRNAs regulate proliferative signaling pathways in pulmonary hypertension

Summary

Principal Investigator: DAVID EMERSON GREEN
Abstract: DESCRIPTION (provided by applicant): Pulmonary hypertension (PH), a progressive disorder causing significant morbidity and mortality, is associated with a variety of diseases commonly afflicting veteran patients. While new PH therapies have improved PH morbidity, the costs of these therapies and the residual PH-associated mortality remain unacceptably high. These observations indicate that new insights into PH pathogenesis and the identification of new therapeutic targets in this disorder are urgently needed. Evolving evidence indicates that activation of the ligand-activated nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPAR), provides a new potential therapeutic target in PH management. Loss of PPAR expression or function is associated with PH in experimental animal and human studies. In contrast, stimulating PPAR attenuated PH in several experimental animal models. The mechanisms by which PPAR exerts its effects in PH remain to be defined and constitute the focus of this proposal. PH is characterized by enhanced proliferation of pulmonary vascular wall cells. Published observations from the mentor's lab demonstrated that PPAR activation attenuates hypoxia-induced alterations in the antiproliferative mediator, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), whose reduced expression may participate in PH pathogenesis. To further examine the mechanisms by which PPAR regulates this antiproliferative mediator, this proposal will focus on the role of microRNAs (miRNA) in PH. miRNAs are small, non-coding (20-22 nucleotide) RNAs that contribute to fine tuning of transcriptional control. Based on preliminary data and in silico analysis, the PI hypothesizes that hypoxic increases in miRNA-21 induce PH and the proliferation of pulmonary vascular wall cells and that PPAR activation attenuates hypoxia-induced alterations in miRNA-21 expression to reduce PH. To explore this hypothesis, the following specific aims will examine the role of miRNAs in hypoxia-induced pulmonary vascular wall cell proliferation in vitro and in PH pathogenesis in vivo and determine the ability of PPAR ligands to attenuate PH by modulating miRNA expression. Aim 1 will examine the role of miRNA-21 in proliferative signaling in hypoxia-exposed pulmonary vascular smooth muscle cells in vitro and in PH in vivo. Following exposure to hypoxic conditions that stimulate human pulmonary artery smooth muscle cell (HPASMC) proliferation, qRT-PCR will be employed to determine miRNA-21 levels. The role of miRNA-21 in HPASMC proliferation will be confirmed with miRNA knockdown or overexpression approaches coupled with functional assays of hypoxic HPASMC proliferation. Corresponding alterations in levels of the putative miRNA- 21 target, PTEN, will be determined. These in vitro findings will be confirmed in an in vivo mouse model of hypoxia-induced PH. Collectively, these studies will determine the role of hypoxia-induced alterations in miRNA-21 expression on the regulation of pulmonary vascular wall cell proliferation in vitro and in vivo. Aim 2 will therapeutically target miRNA-21 with PPAR ligands to attenuate hypoxia-induced cell proliferation and PH. This aim will employ the in vitro and in vivo models used in Aim 1, except experiments will include treatments with a range of doses and durations of pharmacological PPAR ligands previously established by the mentor's lab. Selected studies will confirm PPAR -regulated miRNA expression and function in models with cell- targeted PPAR overexpression or knockout. The successful execution of these innovative studies will not only provide critical new insights into the role of miRNA regulation in PH pathogenesis and therapy but will provide the applicant broad-based training in pulmonary vascular biology that will facilitate his long-term career goals of becoming a successful physician-scientist in the VA system.
Funding Period: 2013-07-01 - 2018-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Molecular mechanisms of downregulated Kv channels in IPAH: Role of microRNA
    Jason X J Yuan; Fiscal Year: 2013
    ..The long-term goal of this study is to define the mechanism underlying the inhibition of Kv channels in IPAH- PASMC and to explore the possibility to target miRNA for developing therapeutic approaches for IPAH. ..
  2. TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth
    Jeffrey S Isenberg; Fiscal Year: 2013
    ....
  3. Regulation of Arginase in Models of Pulmonary Hypertension
    Bernadette Chen; Fiscal Year: 2013
    ....
  4. The Role of Vascular MR-Regulated Genes in Vascular Function and Disease
    Iris Z Jaffe; Fiscal Year: 2013
    ..abstract_text> ..
  5. Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
    Rama Natarajan; Fiscal Year: 2013
    ..The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis. ..
  6. Neprilysin and Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms
    EDWARD CHARLES DEMPSEY; Fiscal Year: 2013
    ....
  7. Toll-like receptor signaling in pathogenesis of pulmonary hypertension
    Yabing Chen; Fiscal Year: 2013
    ....
  8. Arterial Stiffness in the Pathogenesis of Human Pulmonary Arterial Hypertension
    LAURA ELIZABETH FREDENBURGH; Fiscal Year: 2013
    ....
  9. Functional linkage of NHE1 and calpain in IPAH
    Larissa A Shimoda; Fiscal Year: 2013
    ..Such information is crucial to advancing treatment and developing new therapeutic options to treat this deadly disease. (End of Abstract) ..
  10. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  11. Role of MicroRNAs 424 and 503 in Pulmonary Arterial Hypertension
    Hyung Joon Chun; Fiscal Year: 2013
    ....
  12. mTOR coordinates cell metabolism, growth and survival in pulmonary hypertension
    Elena Goncharova; Fiscal Year: 2013
    ..abstract_text> ..
  13. Tadalafil for Pulmonary Hypertension Associated with Chronic Lung Disease
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..If successful, this treatment option may improve quality of life and outcomes for the large number of veterans afflicted with PH due to COPD. ..
  14. Pulmonary Hypertension in Genetically Modified Mice
    Marlene Rabinovitch; Fiscal Year: 2013
    ..Our studies could lead to using elastin degradation products as biomarkers of early and progressive PAH, and to new treatments that stabilize the elastin matrix. ..
  15. 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) ..
  16. 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. ..
  17. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  18. Mechanisms and Consequences of Reduced PPAR gamma in Pulmonary Hypertension
    C Michael Hart; Fiscal Year: 2013
    ..The results of this proposal can thereby define novel and effective therapeutic strategies to regulate programs of gene expression involved in PH pathogenesis. ..
  19. Mitochondria-Derived Reactive Oxygen Species and Nox4 in Pulmonary Hypertension
    SHERRY ADESINA; Fiscal Year: 2013
    ..This award will prepare me for my long-term goal of becoming an independent academic researcher. ..
  20. Role of the PDGF signaling pathway in pulmonary artery hypertension
    Akiko Hata; Fiscal Year: 2013
    ..In SA2, we will test the efficacy of perturbation of miR-24 in animal models of PAH. Finally, SA3 will demonstrate the deregulation of miR-24 in human PAH patients and identify novel targets of miR-24. ..
  21. Protein Phosphatase Inhibitor-1 and vascular smooth muscle cell function
    Lahouaria Hadri; Fiscal Year: 2013
    ..Defining the mechanisms of I-1 and its physiological consequences, will be of great relevance in the analysis and future proposal of therapies to prevent and perhaps reverse neointima formation after angioplasty. ..
  22. Role of Bone Morphogenetic Protein 4 in Hypoxic Pulmomary Hypertension
    Jian Wang; Fiscal Year: 2013
    ..Our study focuses on investigation of whether and how BMP4 regulates this process, which, if successful, will lead to improved methods of pharmacological prevention and treatment of this lethal complication of chronic lung diseases. ..
  23. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  24. 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. ..
  25. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    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. ..
  26. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..