Tuberin &hamartin in rapamycin-sensitive &insensitive smooth muscle cell growth

Summary

Principal Investigator: Usamah S Kayyali
Abstract: DESCRIPTION (provided by applicant): Smooth muscle cell proliferation is the hallmark of many diseases, including pulmonary hypertension, asthma, lymphangioleiomyomatosis, and tuberous sclerosis complex (TSC). Hamartin and tuberin are highly expressed in smooth muscle and are encoded by the tumor suppressor genes, Tuberous Sclerosis Complex-1 and -2 respectively (TSC1;TSC2). Tumor suppressor function is dependent upon complex formation between hamartin and tuberin. Functional loss of either hamartin or tuberin leads to identical cellular effects: Increased levels of the G protein, GTP-Rheb (Ras homolog enriched in brain), with downstream constitutive activation of mTOR (mammalian target of rapamycin), S6Kinase (S6K) and S6, leading to increased cellular growth. We show that independent of S6K-S6 activation, the cellular hyperproliferation observed in pulmonary artery vascular smooth muscle cells (PaVSMCs), where the TSC1/TSC2 complex is disrupted, is also associated with (i) rapamycin-sensitive effects that involve mitochondrial-derived superoxide anion (O2.-) production and reduced mitochondrial-mediated apoptosis and (ii) rapamycin-insensitive activation and co-localization of the G proteins, Rheb and Rho A. Recent data suggests that low grade pulmonary hypertension occurs in women diagnosed with pulmonary LAM, a disease where TSC2 is functionally deficient and we have observed increased pulmonary pressures in a murine model where TSC1 is conditionally knocked out in vascular smooth muscle. Our hypothesis is that in PaVSMCs, TSC1/TSC2 complex dysfunction results in: (i) rapamycin- sensitive altered mitochondrial function that promotes redox-regulated apoptosis, (ii) rapamycin- insensitive activation of Rheb and RhoA that also promotes growth, and (iii) a phenotype that promotes the development of pulmonary hypertension. To address this hypothesis , our Specific Aims are: 1) To study the regulation by the TSC1/TSC2 complex of the rapamycin-sensitive generation of mitochondrial O2.- and the downstream effectors that are pertinent to PaVSMC growth;2) To study the regulation by the TSC1/TSC2 complex of the rapamycin-insensitive activation of the G proteins Rheb and RhoA and their downstream effectors pertinent to PaVSMC growth and 3) To study the effect of TSC1/TSC2 complex disruption on the development of pulmonary hypertension in vivo. These studies will lead to a new understanding of how the TSC1/TSC2 complex controls the proliferation of pulmonary vascular smooth muscle. We hope that our studies will lead to the development of new therapies for diseases characterized by SMC proliferation like pulmonary hypertension. PUBLIC HEALTH RELEVANCE: Smooth muscle cell (SMC) growth is the hallmark of pulmonary hypertension. We plan to study the regulation of SMC growth by two SMC proteins, hamartin and tuberin. The purpose of the proposed studies is to improve our understanding of the mechanisms that lead to uncontrolled growth in smooth muscle and to develop new targets for the treatment of pulmonary hypertension.
Funding Period: 2009-09-15 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin
    Amy J Malhowski
    Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, No 257, 800 Washington Street, Boston, MA 02111, USA
    Hum Mol Genet 20:1290-305. 2011

Detail Information

Publications1

  1. pmc Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin
    Amy J Malhowski
    Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, No 257, 800 Washington Street, Boston, MA 02111, USA
    Hum Mol Genet 20:1290-305. 2011
    ....

Research Grants30

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  2. 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. ..
  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. Chronic hypoxia and pH homeostasis in pulmonary myocytes
    Larissa A Shimoda; Fiscal Year: 2013
    ....
  5. Regulation of Arginase in Models of Pulmonary Hypertension
    Bernadette Chen; Fiscal Year: 2013
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  6. Ca2+ Regulation in Chronic Hypoxic Pulmonary Hypertention
    JAMES SK SHAM; Fiscal Year: 2013
    ..The information generated by the proposed experiments may help to develop new treatments for pulmonary hypertension. ..
  7. Impaired AMPK activity contributes to vascular pathogenesis associated with PH
    Judy R Creighton; Fiscal Year: 2013
    ..2] Changes in AMPK ????? expression patterns correlate with segment specific vascular disease in PH. ..
  8. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  9. Regulation of Neurogenesis in TSC by mTORC1 and mTORC2
    Kevin C Ess; Fiscal Year: 2013
    ..Our proposal is expected to define abnormal mTORC1 and mTORC2 signaling pathways in mouse and human cells and lead to the development of much more effective therapies for patients with TSC. ..
  10. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  11. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  12. 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. ..
  13. Vascular Smooth Muscle Function in Pulmonary Hypertension
    Nikki L Jernigan; Fiscal Year: 2013
    ..Ultimately, such knowledge has the potential to provide new directions in pulmonary hypertension therapy. ..
  14. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  15. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  16. 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. ..
  17. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  18. 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. ..
  19. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  20. Regulation of the mTOR Pathway By Nutrients
    David M Sabatini; Fiscal Year: 2013
    ..Furthermore, some of the signaling mechanisms we uncover may serve in the future as targets for drug development. ..
  21. The Serotonin Transporter in Pulmonary Arterial Hypertension
    Kelly Chin; Fiscal Year: 2013
    ....
  22. 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. ..