Role of FoxO1 in Lipid Metabolism

Summary

Principal Investigator: REBECCA ANNE HAEUSLER
Abstract: DESCRIPTION (provided by applicant): Candidate - The overall goal of this K99/R00 proposal is to facilitate my transition from a training track (undergraduate, PhD, and postdoctoral) to a leadership track as a fully independent academic investigator. My goals for the K99 component are to develop skills that are still lacking but necessary to my research goals, cultivate a substantial base of knowledge and preliminary data, and acquire a tenure-track assistant professorship. I have laid out an extensive training plan to help me achieve these goals. This plan includes learning new techniques, coursework, presenting my work at local and international conferences, and learning to be a mentor. I will be guided by an invaluable group of senior investigators, including my mentor, three scientific advisors, three external collaborators, and a career development advisor. My goals for the R00 are to use my unique skill set, which bridges two fields of biomedical research, to launch a productive and successful laboratory. During this time, I plan to recruit students and assistants, collect data, publish my work, identify mentors and advisors in my new environment, develop new collaborations, and apply for an R01. My long- term career goals as an academic investigator are to advance knowledge in the field of metabolic diseases, develop new medical treatment and diagnostic options for patients, train high quality investigators, and to develop fruitful collaborations with investigators in the same and other disciplines. Environment - Columbia University is among the finest academic institutions nationwide, by almost any measure. The productivity on campus is reflected in its ranking as #11 among universities, colleges, and private institutions in federal research funding. Columbia's Department of Medicine has a long history of scientific excellence, and is currently home to outstanding investigators in the fields related to my research: lipid metabolism, atherosclerosis, diabetes, and obesity. With this rich environment, I have full access to all of the resources to perform the proposed research. My mentor, advisors, and collaborators, both at Columbia and elsewhere, constitute a crucial aspect of this proposal. During the K99, I plan to take advantage of their expertise and guidance, with regard to science and career. Research - Cardiovascular disease (CVD) remains the leading cause of death and disability in the country. Available therapies are inadequate, in part because they fail to redress the primary defects in many patients at high risk for CVD. The metabolic syndrome and diabetes are two major risk factors for CVD, and they are associated with a characteristic constellation of lipid metabolic abnormalities that accelerate atherogenesis, including high serum triglycerides, low high-density lipoprotein cholesterol (HDL-C), and accumulation of liver fat, defects that are poorly responsive to current hypolipidemic agents. Understanding the physiological and molecular mechanisms of these defects will expand the repertoire of targets for atherosclerosis treatment and prevention. However, a crucial gap in our knowledge exists: we do not know why triglycerides rise and HDL-C falls in the natural history of the metabolic syndrome. The liver is o critical interest, because it straddles both glucose and lipid metabolism, and it has become clear that the notion of "insulin resistance" can not explain all of the metabolic defects present in the liver. I am interested in exploring non-canonical connections among signaling pathways that drive hepatic glucose and lipid metabolism, in the hope of enlisting new players in the therapeutic approach to CVD. In preliminary data, I demonstrate a heretofore unknown link between the canonical Akt-FoxO pathway, bile acid (BA) composition, and lipid synthesis. To investigate this pathway, I propose three aims: in Aim 1, I will examine the role of the BA receptor FXR in linking FoxO-dependent transcription with lipogenesis;in Aim 2, I will investigate the requirement for the oxysterol receptor LXR and the role of cholesterol in this process;and in Aim 3, I will study the effect of FoxO- dependent BA composition on the activity of the cell surface BA receptor, TGR5, in peripheral tissues, as a potential extra-hepatic mechanism of impaired lipid metabolism. These data will provide a roadmap to design new therapeutic interventions in the treatment of dyslipidemia within the rapidly growing population of people with the metabolic syndrome.
Funding Period: 2012-06-01 - 2014-02-28
more information: NIH RePORT

Top Publications

  1. pmc Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, New York
    Diabetes 62:4184-91. 2013

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  4. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
  5. CEACAM1: A link between metabolic and cardiovascular diseases
    Sonia M Najjar; Fiscal Year: 2013
  6. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
  7. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
  8. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
  9. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
  10. CEACAM AND INSULIN ACTION
    Sonia M Najjar; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, New York
    Diabetes 62:4184-91. 2013
    ..These findings suggest a role for 12α-hydroxylated BAs in metabolic abnormalities in the natural history of T2D and raise the possibility of developing insulin-sensitizing therapeutics based on manipulations of BA composition. ..

Research Grants31

  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. 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. ..
  3. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  4. 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. ..
  5. 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. ..
  6. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
    ....
  7. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  8. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  9. 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. ..
  10. CEACAM AND INSULIN ACTION
    Sonia M Najjar; Fiscal Year: 2013
    ..This should provide a critical test of the causative effect of hyperinsulinemia on insulin resistance, and identify CEACAM1 as a tractable drug target for the development of medications to combat altered metabolic conditions. ..
  11. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  12. 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. ..