Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism

Summary

Principal Investigator: UTPAL BHAGIRATH PAJVANI
Abstract: DESCRIPTION (provided by applicant): This proposal describes a five year plan for Utpal Pajvani to transition to an independently-funded investigator, a clinician/scientist with a focus on translational research. Dr. Pajvani received MD and PhD degrees from the Albert Einstein College of Medicine in 2005, the latter degree earned in defining the biochemistry of the adipocyte-secreted hormone, adiponectin, and subsequently performed medical training in Internal Medicine and Endocrinology at Columbia University. Dr. Pajvani's clinical training cemented his intent to translate research to benefit patients, whether it be through the discovery of a novel pathway in the development of insulin resistance, or application of a known therapeutic agent from cancer biology to the metabolic syndrome. The goals of the proposed training are to provide training and mentoring to prepare Dr. Pajvani for an independent research career, and additionally, to answer fundamental, lingering questions on the pathogenesis of insulin resistance and its treatment. Type 2 diabetes is associated with obesity and generalized insulin resistance;currently available insulin sensitizers are only partially effective at improving glucose disposal in skeletal muscle and suppressing glucose production in liver. A more detailed knowledge of pathways that influence insulin resistance is necessary to identify new targets for the development of drugs that will assist in the management of diabetic patients. In this application, Dr. Pajvani describes preliminary data that reveal the novel role of the Notch family of transmembrane receptors, traditionally thought only to mediate normal development and thereafter remain quiescent unless inappropriately activated in cancer, in regulation of hepatic metabolism through its interaction with FoxO1, a transcription factor known to modulate insulin sensitivity. Through detailed metabolic analyses in compound haploinsufficient (FoxO1:Notch1) mice, Dr. Pajvani and one of his mentors, Domenico Accili, determined that genetic inhibition of hepatic Notch action demonstrated beneficial effects in both glucose and lipid homeostasis. These effects were recapitulated by pharmacologic inhibitors of Notch action, which were able to markedly improve glucose tolerance in diet- induced and genetic models of obesity. Dr. Pajvani proposes in this application (i) to characterize the Notch pathway in states of insulin resistance, (ii) to determine the mechanism of the differential effects of Notch and its pharmacological inhibitors on glucose and lipid metabolism, and (iii) to study the effects of inhibition of Notch signaling with pharmacologic tools (small molecule inhibitors or monoclonal antibodies) or other genetic mouse models of Notch hypofunction. Additionally, Dr. Pajvani proposes an observational clinical study to determine if hepatic expression of Notch pathway components correlates with measures of insulin resistance, hyperlipidemia and/or hepatic steatosis in obese and diabetic patients. The goal of these studies is to demonstrate whether inhibition of Notch signaling is a viable therapeutic target in the correction of hyperglycemia and dyslipidemia characteristic of obesity-induced insulin resistance and the metabolic syndrome. Dr. Pajvani's overall career objective is to be able to translate the seminal discoveries made at the bench into therapeutic application in patients he sees at the Naomi Berrie Diabetes Center and inpatient Endocrinology and Metabolism service at Columbia University Medical Center. His patient care responsibilities, beyond providing personal satisfaction, allow Dr. Pajvani to approach scientific questions with pragmatism and with a sense of urgency. These same responsibilities encourage continued research training, as outlined in this application. The training he still needs to understand and fruitfully apply epidemiology and statistical methods in the design and analysis of clinical research studies, can best be addressed through continued study at Columbia University. Furthermore, the scientific knowledge required to integrate hepatic insulin signaling on glucose and lipid metabolism, as well as the multifaceted aspects of FoxO1 and Notch biology, can best be addressed through his choice of mentors (Drs. Domenico Accili and Jan Kitajewski) and advisors (Drs. Henry Ginsberg, Ira Goldberg and Robin Goland), all respected investigators who value mentoring young and aspiring faculty members. Finally, the Columbia University Medical Center environment brings together access to a diverse patient population and all the facilities and faculty developmental tools that Dr. Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community.
Funding Period: 2011-09-15 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability
    Utpal B Pajvani
    Department of Medicine, Columbia University, New York, New York, USA
    Nat Med 19:1054-60. 2013
  2. pmc Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease
    Luca Valenti
    Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Internal Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca Granda, Milano, Italy
    Diabetes 62:4052-62. 2013

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
  3. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
  4. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
  5. LKB1- AMPK pathway regulation of glucose metabolism and metformin action in liver
    REUBEN JAMES SHAW; Fiscal Year: 2013
  6. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  7. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
  8. UMass Mouse Metabolic Phenotyping Center
    Jason K Kim; Fiscal Year: 2013
  9. Coenzyme A Regulation of Metabolism
    Suzanne Jackowski; Fiscal Year: 2013
  10. The role of nicotinamide N-methyltransferase in glucose and lipid homeostasis
    Pavlos Pissios; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability
    Utpal B Pajvani
    Department of Medicine, Columbia University, New York, New York, USA
    Nat Med 19:1054-60. 2013
    ..These data identify Notch as a therapeutically actionable branch point of metabolic signaling at which Akt activation in the liver can be uncoupled from hepatosteatosis. ..
  2. pmc Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease
    Luca Valenti
    Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Internal Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca Granda, Milano, Italy
    Diabetes 62:4052-62. 2013
    ..In summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease. ..

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. 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. ..
  3. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  4. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  5. LKB1- AMPK pathway regulation of glucose metabolism and metformin action in liver
    REUBEN JAMES SHAW; Fiscal Year: 2013
    ..These studies disecting the role of the LKB1- AMPK pathway in liver will increase the understanding of how existing widely used diabetes modalities work, and identify critical new targets for future type 2 diabetes therapeutics. ..
  6. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  7. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  8. UMass Mouse Metabolic Phenotyping Center
    Jason K Kim; Fiscal Year: 2013
    ....
  9. Coenzyme A Regulation of Metabolism
    Suzanne Jackowski; Fiscal Year: 2013
    ..This original approach to reprogramming intermediary metabolism will define the role of CoA in hepatic gluconeogenesis and provide insight into the factors that give rise to human disorders of lipid and glucose homeostasis. ..
  10. The role of nicotinamide N-methyltransferase in glucose and lipid homeostasis
    Pavlos Pissios; Fiscal Year: 2013
    ..This proposal has direct relevance to the NIDDK mission and will establish NNMT as a potential new candidate gene for the treatment of the metabolic syndrome. ..
  11. MULTI-TISSUE MULTI-TRACER METABOLIC PHENOTYPING OF DIABETES WITH PRE-CLINICAL PET
    KOORESH ISAAC SHOGHI; Fiscal Year: 2013
    ....
  12. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  13. Atypical PKC Knockout Models: Effect on Glucose and Lipid Homeostasis
    Robert V Farese; Fiscal Year: 2013
    ..abstract_text> ..
  14. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  15. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  16. Insulin Signaling and Metabolic Effects through CLK2 Kinase
    Pere Puigserver; Fiscal Year: 2013
    ....
  17. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  18. 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. ..
  19. Regulation of Bile Acid Synthesis by Nuclear Receptors
    John Y L Chiang; Fiscal Year: 2013
    ..The long-term objectives of this research are to elucidate the molecular mechanism of regulation of CYP7A1 and bile acid metabolism, and pathogenesis and treatment of metabolic diseases such as fatty liver disease, diabetes and obesity. ..
  20. Role of Chromogranin A in Metabolic Syndrome
    Sushil K Mahata; Fiscal Year: 2013
    ..2. Evaluate the potential therapeutic effects of CST and its variants on insulin sensitivity and baroreflex sensitivity and heart rate variability in high fat diet-induced insulin resistant and in db/db diabetic mice. ..
  21. CEACAM1: A link between metabolic and cardiovascular diseases
    Sonia M Najjar; Fiscal Year: 2013
    ..Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention. ..
  22. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
    ....
  23. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
    ....