The protein family of neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) together with their receptors (trkA, trkB, trkC) represents the best known group of neurotrophic factors and receptors. The neurotrophins act on various populations of central neurons which undergo degeneration in Alzheimer's disease (AD). NGF has been proposed as experimental treatment for AD based on its robust trophic influence on cholinergic neurons of the basal forebrain and the cholinergic neuron atrophy in AD. However, given the selectivity for NGF for cholinergic neurons, other neurotrophic factors will be necessary to protect all populations vulnerable in AD. The program project grant aims at identifying such molecules. The studies of specific aim #1 and #2 of this project will generate new neurotrophic factors and neurotrophins with different spectra of receptor selectivities. Mutants of neurotrophins and modified neurotrophins are produced and tested for activities in receptor binding and functional receptor assays. These molecules will be tested in studies of Projects 2 and 3 for biological activity in vitro and in vivo, in animal models mimicking the atrophy of specific neuronal populations vulnerable in AD. The studies proposed in specific aims #1 and #2 pursue the scientific goal to understand at a detailed molecular level the interaction between neurotrophins and their receptors. In particular, proposed studies with neurotrophic heterodimers will test the currently widely held believe that a single neurotrophin homodimer interacts with two trk-type receptor molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG010480-06
Application #
2334207
Study Section
Project Start
Project End
Budget Start
1995-10-01
Budget End
1996-09-30
Support Year
6
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wong, Philip C; Cai, Huaibin; Borchelt, David R et al. (2002) Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 5:633-9
Wong, P C; Cai, H; Borchelt, D R et al. (2001) Genetically engineered models relevant to neurodegenerative disorders: their value for understanding disease mechanisms and designing/testing experimental therapeutics. J Mol Neurosci 17:233-57
Qiao, X; Chen, L; Gao, H et al. (1998) Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci 18:6990-9
Knusel, B; Gao, H; Okazaki, T et al. (1997) Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 78:851-62
Hughes, P E; Alexi, T; Hefti, F et al. (1997) Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun. Neuroscience 78:1037-49
Sukhov, R R; Cayouette, M H; Radeke, M J et al. (1997) Evidence that perihypoglossal neurons involved in vestibular-auditory and gaze control functions respond to nerve growth factor. J Comp Neurol 383:123-34
Koliatsos, V E; Price, D L (1996) Axotomy as an experimental model of neuronal injury and cell death. Brain Pathol 6:447-65
Qiao, X; Hughes, P E; Venero, J L et al. (1996) NT-4/5 protects against adrenalectomy-induced apoptosis of rat hippocampal granule cells. Neuroreport 7:682-6
Chan, K M; Lam, D T; Pong, K et al. (1996) Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion. Neurochem Res 21:763-7
Qiao, X; Hefti, F; Knusel, B et al. (1996) Selective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia. J Neurosci 16:640-8

Showing the most recent 10 out of 43 publications