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.
Status | Finished |
---|---|
Effective start/end date | 4/1/01 → 6/30/11 |
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.