Heightened expression of both a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and a survival peptide, insulin-like growth factor-I (IGF-I), occurs in numerous inflammatory conditions of the central nervous system (CNS), including Alzheimer's Disease, cerebral ischemia and the AIDS-dementia complex. Conventional roles for these two proteins are neuroprotection by IGF-I and neurotoxicity by TNF-alpha. Preliminary findings suggest that (a) Picogram, non-toxic amounts of TNF-alpha markedly reduce the capacity of IGF-I to promote survival of primary cerebellar granule neurons and (b) TNF-alpha inhibition of IGF-I and TNF-alpha in the CNS were originally mediated through the p55 TNF-alpha receptor. Although the mechanisms of action for IGF-I and TNF-alpha in the CNS were originally established as disparate and unrelated, we hypothesize that TNF-alpha also promotes neurodegeneration through inhibition of IGF-I survival signaling. The ultimate goal of this project is to identify and characterize a novel form of neurodegeneration that may add to the existing, incomplete model of neuronal death and inflammation. TNF-alpha may suppress the ability of IGF-I to initiate on all of three essential components of IGF-I receptors survival signaling; tyrosine auto phosphorylation of the IGF-I receptor beta-chain, tyrosine phosphorylation of insulin receptor substrate-2 (IRS-2) and activation of the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). In order to confirm and characterize these preliminary observations, we propose to: (a) Identify possible neurodegeneration through TNF-alpha inhibition of IGF-I survival promotion in primary murine granule neurons; (b) Determine which TNF-alpha receptor isoform (p55 or p75) mediates interference with IGF-I survival signaling; and (c) Explore the receptor signaling mechanism by which TNF-alpha inhibits IGF-I survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH012558-03
Application #
6538338
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (02))
Program Officer
Curvey, Mary F
Project Start
2002-06-01
Project End
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$27,613
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820