DF/HCC Program Affiliation

Neuro-Oncology

Research Abstract

The primary objective of our lab is to investigate the biological function(s) of NRP/B, a recently discovered and characterized novel neuronal nuclear matrix protein, particularly its role in neuronal differentiation. Our studies indicate that NRP/B is an early expressed gene in fetal brain and its expression is developmentally regulated in the nervous system during mouse embryogenesis. In adult brain, NRP/B is specifically expressed in primary neurons and its level of expression is upregulated during neuronal differentiation. Overexpression of NRP/B significantly induces growth arrest and augments neuronal process formation, while treatment with antisense NRP/B oligodeoxynucleotides inhibits neurite development during in vitro neuronal differentiation. Microinjection of NRP/B antibodies, which inhibits neurite outgrowth of PC12 cells in response to Neuronal Growth Factor (NGF) stimulation, while transfection of NRP/B cDNA, which results in overexpression of NRP/B protein, induces grow arrest and enhances neurite outgrowth of PC12 cells. In addition, NRP/B interacts with the retinoblastoma protein p110RB. We aim to determine whether: (1) NRP/B is involved in neuronal differentiation by interacting with key molecules in neuronal cells; and (2) NRP/B is involved in cell cycle withdrawal and/or in the maintenance of neuronal differentiation status through its interaction with key molecules, such as p110RB. These studies are designed to provide further insights into NRP/B function(s) in the context of neuronal differentiation.

Another interest is to study the blood brain barrier endothelial cells. The integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological abnormalities in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis and abnormalities in the permeability of the BBB. The processes by which HIV causes these pathological conditions are not well understood. We aim to characterize mechanisms of brain microvascular endothelial cell (BMEC) injury in the HIV-infected host. The HIV-1 TAT protein is actively released into the extracellular environment, entering nearby cells and transactivating HIV-LTR and endogenous genes. HIV-1 TAT is angiogenic in vivo, is found in the serum of HIV-infected patients and is detected in mononuclear cells within the brains of patients with HIV encephalitis. HIV-1 TAT-mRNA levels are elevated in the brains of patients with HIV-induced dementia. We plan to characterize signaling pathways in human primary BMEC that are triggered by HIV-1 TAT, which regulates these pathways. These studies should provide insights into preventive and/or therapeutic strategies to sustain BBB integrity in HIV-infected patients.

Publications

• Jiang S, Seng S, Avraham HK, Fu Y, Avraham S.Process Elongation of Oligodendrocytes Is Promoted by the Kelch-related Protein MRP2/KLHL1.J Biol Chem 2007 Apr 20;282(16):12319-29.
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• Lee TH, Seng S, Li H, Kennel SJ, Avraham HK, Avraham S.Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis.J Biol Chem 2006 Dec 29;281(52):40450-60.
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• Seng S, Avraham HK, Jiang S, Venkatesh S, Avraham S.KLHL1/MRP2 mediates neurite outgrowth in a glycogen synthase kinase 3beta-dependent manner.Mol Cell Biol 2006 Nov;26(22):8371-84.
  16982692
• Park SY, Li H, Avraham S.RAFTK/Pyk2 regulates EGF-induced PC12 cell spreading and movement.Cell Signal 2007 Feb;19(2):289-300.
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• Kaminski R, Zagozdzon R, Fu Y, Mroz P, Fu W, Seng S, Avraham S, Avraham HK.Role of SRC kinases in Neu-induced tumorigenesis: challenging the paradigm using Csk homologous kinase transgenic mice.Cancer Res 2006 Jun 1;66(11):5757-62.
  16740714
• Lee BC, Avraham S, Imamoto A, Avraham HK.Identification of the nonreceptor tyrosine kinase MATK/CHK as an essential regulator of immune cells using Matk/CHK-deficient mice.Blood 2006 Aug 1;108(3):904-7.
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• Jiang S, Avraham HK, Kim TA, Rogers RA, Avraham S.Receptor-type PTP-NP inhibition of Dynamin-1 GTPase activity is associated with neuronal depolarization.Cell Signal 2006 Sep;18(9):1439-46.
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• Park SY, Schinkmann KA, Avraham S.RAFTK/Pyk2 mediates LPA-induced PC12 cell migration.Cell Signal 2006 Jul;18(7):1063-71.
  16199135
• Jiang S, Avraham HK, Park SY, Kim TA, Bu X, Seng S, Avraham S.Process elongation of oligodendrocytes is promoted by the Kelch-related actin-binding protein Mayven.J Neurochem 2005 Mar;92(5):1191-203.
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• Soltysik-Espanola M, Rogers RA, Jiang S, Kim TA, Gaedigk R, White RA, Avraham H, Avraham S.Characterization of Mayven, a novel actin-binding protein predominantly expressed in brain.Mol Biol Cell 1999 Jul;10(7):2361-75.
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• Yamashita H, Avraham S, Jiang S, Dikic I, Avraham H.The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells.J Biol Chem 1999 May 21;274(21):15059-65.
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