CNS aging and neurodegenerative pathologies such as Alzheimer's disease are characterized by neuronal loss induced by a number of factors including decreased trophic factor signaling. The neurotrophins, NGF, BDNF, and NT-3 sustain survival of those neurons that are often affected by binding to specific tyrosine kinase receptors (trk), as well as to a common low affinity receptor (p75) whose function is not clear. NTs have been proposed as the basis for treatments to prevent neurodegeneration. A successful development of NT treatment requires a thorough characterization of the signal elements that transduce NT trophic action. This project focuses on the NGF-associated signal pathways involved in NGF mediated rescue from apoptosis. It is proposed that the stimulation of PKC-zeta and the activation of NF-kappa B are signal elements common to the activation of both NGF receptors. Using immortalized nigral and cerebellar cultured neurons transfected with either or both NGF receptors, Aim 1 will test whether binding to either Trk A or p75 may be sufficient to rescue cells from serum starved apoptosis.
Aim 2 will test whether there are signal molecules associated with p75 that can affect apoptosis.
Aim 3 will test whether PKC zeta activation or NF-kappa B translocation are signals common to both trk A and p75 receptors that are essential for rescue from apoptosis.
Aim 5 will test whether the apoptosis which occurs in the aged rodent is associated with altered PKC or NF-kB signaling and confirm the in vitro observations. These experiments will elucidate mechanisms that mediate NT support of neurons and provide useful information as to the development of therapies to counteract age and pathology associated neuronal apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AG013945-02
Application #
2683174
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Oliver, Eugene J
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Wang, Jigong; Cochran, Victoria; Abdi, Salahadin et al. (2008) Phenyl N-t-butylnitrone, a reactive oxygen species scavenger, reduces zymosan-induced visceral pain in rats. Neurosci Lett 439:216-9
Kim, Hee Kee; Park, Soon Kwon; Zhou, Jun-Li et al. (2004) Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 111:116-24
Lanlua, P; Decorti, F; Gangula, P R et al. (2001) Female steroid hormones modulate receptors for nerve growth factor in rat dorsal root ganglia. Biol Reprod 64:331-8
Macdonald, N J; Decorti, F; Pappas, T C et al. (2000) Cytokine/neurotrophin interaction in the aged central nervous system. J Anat 197 Pt 4:543-51
Macdonald, N J; Taglialatela, G (2000) Tumor necrosis factor-alpha and nerve growth factor synergistically induce iNOS in pheochromocytoma cells. Neuroreport 11:3453-6
Bickford, P C; Chadman, K; Williams, B et al. (1999) Effect of normobaric hyperoxia on two indexes of synaptic function in Fisher 344 rats. Free Radic Biol Med 26:817-24
Yallampalli, S; Micci, M A; Taglialatela, G (1998) Ascorbic acid prevents beta-amyloid-induced intracellular calcium increase and cell death in PC12 cells. Neurosci Lett 251:105-8
Taglialatela, G; Kaufmann, J A; Trevino, A et al. (1998) Central nervous system DNA fragmentation induced by the inhibition of nuclear factor kappa B. Neuroreport 9:489-93
Taglialatela, G; Foreman, P J; Perez-Polo, J R (1997) Effect of a long-term nerve growth factor treatment on body weight, blood pressure, and serum corticosterone in rats. Int J Dev Neurosci 15:703-10