Ceramide and acute phase protein elevation during aging

Grants and Contracts Details

Description

Our lab has long standing interest in the mechanisms leading to the state of chronic, low-grade inflammation, which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to one of the major inflammatory cytokines, Interleukin 113 (IL-i l~) is significantly augmented during aging causing an excessive production of IGFBP1, a secretory hepatic protein that binds to the Insulin-like Growth Factor 1 (lGFi) and neutralizes its bioactivity. This hyperresponsiveness is caused by intrinsic activation of neutral sphingomyelinase 2 in liver and accumulation of its product, ceramide, an evolutionary conserved second messenger, which mediates cellular stress response. Here we hypothesize that this IL- 113 hyperresponsiveness impairs the insulin signaling pathway in liver. First, we will investigate how aging-associated IL-i 13 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades P13K, Akt-i, and Foxoi (for insulin), and ceramide, IRAK-i and JNK (for IL-i(3). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young, aged and aged calorie restricted rats and mice will be used. The regulation of IGFBP1 promoter by the two pathways will be investigated in H4IIE cells. These molecular studies will be complemented by assays of insulin- and IGFBP1-depndent functions in vivo, which include tests of IGF1 bioactivity, muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer.
StatusFinished
Effective start/end date4/1/016/30/11

Funding

  • National Institute on Aging: $377,290.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.