Aging as a Risk Factor and Target for Prevention of Liver Cancer

Information

  • Research Project
  • 10270682
  • ApplicationId
    10270682
  • Core Project Number
    P01AG073084
  • Full Project Number
    1P01AG073084-01
  • Serial Number
    073084
  • FOA Number
    PAR-19-314
  • Sub Project Id
  • Project Start Date
    9/15/2021 - 2 years ago
  • Project End Date
    8/31/2026 - 2 years from now
  • Program Officer Name
    GUO, MAX
  • Budget Start Date
    9/15/2021 - 2 years ago
  • Budget End Date
    8/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    9/14/2021 - 2 years ago

Aging as a Risk Factor and Target for Prevention of Liver Cancer

PROJECT SUMMARY ? OVERALL The incidences of liver cancer (primarily hepatocellular carcinoma (HCC)) are increasing and disease outcome is poor. Consequently, there is an urgent need for new therapies and better preventive strategies. Age is a major risk factor for HCC. In line with the geroscience hypothesis, we hypothesize that aging drives a dysfunctional mitochondrial, epigenetic and metabolic network that promotes and exacerbates age-associated dysregulation of immune function and inflammation in liver. Loss of homeostasis across multiple systems is permissive for neoplastic liver disease. We further hypothesize that dysregulated chronic interferon signaling is central to this pathogenic network. We will dissect this network and test the consequence of chronic interferon signaling, to understand why the incidence of liver cancer increases with age. We will also investigate approaches that target this network for their ability to prevent and combat liver cancer. Our overall specific objectives are: Objective 1. Investigate age-associated changes to mitochondria, chromatin, metabolism (specifically, bile acids) and innate and adaptive immunity, their causal role in HCC and underlying mechanisms. Objective 2. Investigate how interactions between these different systems and age-dependent dysregulation of these interactions contributes to HCC. Objective 3. Test the hypothesis that at least some of these age-associated alterations and consequent predisposition to HCC are dependent on chronic interferon signaling in aged tissue. Objective 4. Investigate approaches that target age dysregulation, for example suppressors of chronic interferon activation, mitohormetic interventions, rapamycin, senolytics, bile acid modulators and immune-modulators, for their ability to suppress the onset of liver cancer and better counter established cancer. Since age is the biggest single risk factor for HCC, it follows that a molecular understanding of the age- dependence of HCC can lead to improved disease management through risk assessment, early detection, prognostication and therapy. Moreover, an understanding of how HCC develops during aging can also lead to preventative interventions. This PPG will define critical molecular mechanisms underpinning age-dependence of HCC. We will also promote approaches for improved risk assessment through application, testing and refinement of a transcriptome-based ?tumorigenic index? to quantitate the risk of HCC. Finally, based on our discoveries, we will test a panel of candidate interventions for those that can prevent and combat HCC.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    P01
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    2022449
  • Indirect Cost Amount
    508933
  • Total Cost
    2531382
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
  • Funding ICs
    NIA:2531382\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZAG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES