| The goal of our research is to understand the molecular mechanisms that underlie programmed
cell death (PCD) in the nervous system. In the developing nervous system, PCD is important for the
proper formation of connections between neurons and target cells. However, when cell death occurs
inappropriately, it may contribute to a wide variety of pathological conditions including neurodegenerative
diseases, neurotoxicity, and stroke.
As a model system, we study a type of cell death called apoptosis that occurs when neurons
are deprived of survival-promoting molecules called neurotrophic factors. Because the death of these
neurons requires ongoing RNA and protein synthesis, we have hypothesized that genes specifically expressed
during PCD are likely to be important components of the cell death program. Consistent with this hypothesis,
we identified several genes that increase in expression during PCD. Presently, we are testing specific
pharmacological and molecular inhibitors of the proteins encoded by these genes for their effects on
neuronal survival. Ultimately, we hope to determine how these proteins are activated during cell death
and how they, in turn, activate downstream events in the cell death program.
A second area of interest involves the identification of the signal transduction events critical
for neuronal survival. Using biochemical and molecular biology techniques, we are testing specific signaling
molecules for their ability to promote neurotrophic factor-independent cell survival. Recently, we demonstrated
requirements for phosphatidylinositol 3-kinase and NF-kB activation in the survival of
neurons. By examining the downstream targets of these proteins, we hope to identify the critical regulators of
neuronal survival.
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Farhana, L., Dawson, M.I., Huang, Y., Zhang, Y., Rishi, A, K., Reddy, K.B., Freeman, R.S., and Fontana, J.A. (2004) Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities. Oncogene 23:1874-1884.
Freeman, R.S., Burch, R.L., Crowder, R.J., Lomb, D.J., Schoell, M.C., Straub, J.A., and Xie, L. (2004) NGF deprivation-induced gene expression: After 10 years, where do we stand? Prog. Brain Res. 146:111-126.
Clifton, D.R., Rydkina, E., Freeman, R.S., and Sahni, S.K. (2005) NF-κB activation during Rickettsia rickettsii infection of endothelial cells involves the activation of catalytic IκB kinases IKKα and IKKß, and phosphorylation/proteolysis of the inhibitor protein IκBα. Infect. Immun. 73:155-165.
Clifton, D.R., Rydkina, E., Huyck, H., Pryhuber, G., Freeman, R.S., Silverman, D.J., Sahni, S.K. (2005) Expression and secretion of chemotactic cytokines IL-8 and MCP- 1 by human endothelial cells after Rickettsia rickettsii infection: Regulation by nuclear transcription factor NF-κB. Int. J. Med. Microbiol. 295:267-278. Freeman, R.S, and Barone, M.C. (2005) Targeting hypoxia-inducible factor (HIF) as a therapeutic strategy for CNS disorders. Current Drug Targets – CNS & Neurological Disorders 4:85-92.
Lee, S., Nakamura, E., Yang, H., Wei, W., Linggi, M.S., Sajan, M.P., Farese, R.V., Freeman, R.S., Carter, B.D., Kaelin Jr., W.G., and Schlisio, S. (2005) Neuronal apoptosis linked to EGLN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer. Cancer Cell 8:155-167.
Xie, L., Johnson, R.S., and Freeman, R.S. (2005) Inhibition
of NGF deprivation-induced death by low oxygen involved suppression
of BIMEL and activation of HIF-1. J.
Cell Biol. 168:911-920.
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