Probing the relevance of the "counter-inflammatory" noncanonical IkB kinases in r

Summary

Principal Investigator: Alan R Saltiel
Abstract: DESCRIPTION (provided by applicant): This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We hypothesize that the noncanonical Ikb kinases IKKe and TBK1 are "counterinflammatory" kinases that keep inflammatory pathways in check while helping to support a positive energy balance. Therefore, inhibition of this pathway selectively wil improve positive energy balance and insulin resistance supported by inflammation. In an effort to begin to test this hypothesis, a high-throughput screen was carried out to identify IKKe inhibitors. The most potent and specific inhibitor discovered was Amlexanox;an older drug originally developed in Japan for the treatment of asthma and allergic rhinitis, and later in the US for aphthous ulcers, but without a well understood mechanism of action. It has been in use since 1987, and has a favorable side effect profile. Rodent data obtained in our laboratory has been very promising, showing exciting metabolic effects with amelioration of insulin resistance, glucose and lipid metabolism along with improvement in hepatic steatosis and an increase in energy expenditure. We now propose an early proof-of concept clinical study to translate our laboratory observations using Amlexanox in humans with 3 specific aims: 1) to test the metabolic efficacy in improvement of glucose and insulin resistance parameters in obese Type 2 diabetics. 2) To test the efficacy on amelioration of hepatic steatosis. 3) To develop biomarkers for treatment of patients with type 2 diabetes by Amlexanox. If successful, this proposal may open the door to a novel treatment pathway for the ever-growing metabolic disturbances that are threatening tens of millions of Americans.
Funding Period: 2013-09-18 - 2015-07-31
more information: NIH RePORT

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
  3. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  4. NUTRITION OBESITY RESEARCH CENTER
    Michael W Schwartz; Fiscal Year: 2013
  5. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
  6. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
  7. Yale Mouse Metabolic Phenotyping Center
    Gerald I Shulman; Fiscal Year: 2013
  8. Vanderbilt Mouse Metabolic Phenotyping Center
    David H Wasserman; Fiscal Year: 2013
  9. UMass Mouse Metabolic Phenotyping Center
    Jason K Kim; Fiscal Year: 2013
  10. Correcting glutathione deficiency to restore mitochondrial fat oxidation in aging
    RAJAGOPAL VISWANATH SEKHAR; Fiscal Year: 2013

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  3. 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. ..
  4. NUTRITION OBESITY RESEARCH CENTER
    Michael W Schwartz; Fiscal Year: 2013
    ..However, over the past several years, Als have tended to focus their research in the following major areas: 1. Body Weight Regulation and Obesity 2. Adipose Tissue Biology and Inflammation 3. Lipids and Atherosclerosis 4. Diabetes ..
  5. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..
  6. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  7. Yale Mouse Metabolic Phenotyping Center
    Gerald I Shulman; Fiscal Year: 2013
    ....
  8. Vanderbilt Mouse Metabolic Phenotyping Center
    David H Wasserman; Fiscal Year: 2013
    ..It requires a staff that is so skilled and committed that scientists are willing to entrust their mice, their research lifelines, with them. ..
  9. UMass Mouse Metabolic Phenotyping Center
    Jason K Kim; Fiscal Year: 2013
    ....
  10. Correcting glutathione deficiency to restore mitochondrial fat oxidation in aging
    RAJAGOPAL VISWANATH SEKHAR; Fiscal Year: 2013
    ..The proposal will also test whether restoration of GSH and NEFA oxidation will result in loss of body fat, intrahepatic fat and intramyocellular fat in elderly humans. ..
  11. Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism
    UTPAL BHAGIRATH PAJVANI; Fiscal Year: 2013
    ..Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community. ..
  12. Genomic Analysis of the genotype-phenotype map
    Simon Tavare; Fiscal Year: 2013
    ..The goal of this project is to increase our understanding of the general principles that underlie the genotype-phenotype map by studying model organisms. ..
  13. Genetic and Metabolic Fingerprints of Coativators "Program Project"
    BERT W O'MALLEY; Fiscal Year: 2013
    ..When complete, this PPG will afford a much greater understanding of NR and coregulator biology and will help define novel therapeutic leverage points for intervention of diseases associated with MS. ..
  14. NPC1L1 and Metabolic Diseases
    Liqing Yu; Fiscal Year: 2013
    ..Given that NPC1L1 is the target of ezetimibe, an FDA-approved intestinal cholesterol absorption inhibitor that is widely used to lower blood cholesterol in humans, these studies have enormous translational potential. ..
  15. 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. ..
  16. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  17. Pathogenesis of the Metabolic Syndrome
    W Timothy Garvey; Fiscal Year: 2013
    ..These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance. ..
  18. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
    ....
  19. 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. ..
  20. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  21. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  22. Effects of recombinant human leptin in nonalcoholic fatty liver disease (NAFLD)
    Elif Arioglu Oral; Fiscal Year: 2013
    ..If our hypotheses are correct, 20% of people with fatty liver disease (those with relative leptin deficiency) may derive direct clinical benefit from implications of our research. ..
  23. 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. ..
  24. 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. ..
  25. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..
  26. 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. ..
  27. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  28. Signaling Pathways in Insulin Action
    Alan R Saltiel; Fiscal Year: 2013
    ..abstract_text> ..