An interdisciplinary approach to elucidate mechanisms of muscle lipotoxicity

Information

  • Research Project
  • 8184449
  • ApplicationId
    8184449
  • Core Project Number
    R24DK092781
  • Full Project Number
    1R24DK092781-01
  • Serial Number
    92781
  • FOA Number
    PAR-08-182
  • Sub Project Id
  • Project Start Date
    9/6/2011 - 12 years ago
  • Project End Date
    8/31/2013 - 10 years ago
  • Program Officer Name
    MARGOLIS, RONALD N
  • Budget Start Date
    9/6/2011 - 12 years ago
  • Budget End Date
    8/31/2013 - 10 years ago
  • Fiscal Year
    2011
  • Support Year
    1
  • Suffix
  • Award Notice Date
    9/6/2011 - 12 years ago

An interdisciplinary approach to elucidate mechanisms of muscle lipotoxicity

We are witnessing a dramatic increase in the prevalence of obesity, which is driving an alarming increase in type 2 diabetes worldwide. Rational therapeutic approaches targeting the early stages of this disease continuum requires a comprehensive understanding of the mechanisms that link insulin resistance to excess caloric consumption. An association between skeletal muscle lipid accumulation, insulin resistance, and impaired glucose metabolism is widely recognized, yet the mechanistic underpinnings of the association remain elusive. Indeed, intramyocellular TAG accumulation can be associated with improved muscle performance and metabolic flexibility. During a period of R24 seed grant support, we have built a unified interdisciplinary research team, conducted feasibility and proof-of-concept studies, and designed a full R24 project to address this problem. We will test the central hypothesis that myocellular lipid accumulation triggers both adaptive and maladaptive (lipotoxic) responses, that these can influence glucose utilization via insulin signaling-dependent and -independent mechanisms, and that a dynamic balance between these responses determines the evolution of muscle insulin resistance. This project, which will harness the combined powers of unbiased chemical biology and functional genomics screening, is composed of five inter-connected Specific Aims. Chemical biology (Aim 1) and functional genomic (Aim 2) screens will be conducted using cultured skeletal myocytes loaded with excess fatty acid. To efficiently assess muscle autonomous vs. non-autonomous effects in vivo, a Drosophila model of obesity will be used to rapidly validate the genes (Aim 3). A Systems Integration Group will oversee the collection, storage, filtering, and analysis of the data generated by the studies of each Aim, to establish prioritized lists of genes, small molecule modifiers, and corresponding target pathways. After initial metabolic classification and prioritization, an iterative process of deep cellular and metabolic characterization together with metabolomic, lipidomic, and transcriptomic profiling, will be conducted to define phenotypic fingerprints or signatures representing adaptive and maladaptive sub-categories or "bins" of relevant myocyte perturbations (Aim 4). The phenotypic signatures will then be compared with similar profiles collected for muscle biopsy specimens from well-characterized human volunteers across a range of fitness and metabolic disease cohorts (Aim 5). The long-term goal of this project is to identify new genes, pathways, and molecular probes relevant to muscle lipotoxicity, serving as a valuable hypothesis-generating resource for the field and establishing a pipeline for drug development and biomarker discovery aimed at the earliest stages of insulin resistance.

IC Name
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
  • Activity
    R24
  • Administering IC
    DK
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    500000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    847
  • Ed Inst. Type
  • Funding ICs
    NIDDK:500000\
  • Funding Mechanism
    Other Research Related
  • Study Section
    ZDK1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD-BURNHAM MEDICAL RESEARCH INSTIT
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES