Bressler Bldg. Rm 4-023
655 W. Baltimore Street
Baltimore, MD 21201
Email:
laurelia@umaryland.edu
Phone:
410-706-3895
Fax:
410-706-2513
Research Interests:
The laboratory studies gene regulation and therapy. Focus is on the modulation of signaling pathways and apoptotic cascades, emphasizing the areas of carcinogenesis, neurotoxicity and cell injury. Development of virus vectors for gene delivery is an area of expertise. Laboratory interest is focused on a gene cloned in our laboratory (H11) and shown to encode an unique small heat shock protein. We have shown that H11 expression is inhibited in some cancers, notably melanoma and prostate cancer, apparently involving aberrant DNA methylation. In these cells, forced H11 expression triggers apoptosis, the first documentation of a pro-apoptotic heat shock protein. Ongoing studies are investigating the regulation of H11 expression, defining signaling pathways that are involved in its ability to trigger apoptosis, and their control. The ability of tet-regulated and vector-delivered H11 to induce tumor cell death in vivo is under investigation.
Ongoing research is also focused on a herpes simplex virus type 2 (HSV-2) gene (known as ICP10PK) that has protein kinase (PK) activity and behaves as an activated growth factor receptor. The mechanism of ICP10PK anti-apoptotic activity is under investigation in various paradigms of neuronal cell death including virus infection, trophic growth support, genetic defects and excitotoxic injury. In the virus infection paradigm, ICP10PK mediated neuroprotection includes activation of the Ras/Raf-1/MEK/ERK pathway resulting in Bag-1 upregulation. The mechanism of ICP10PK neuroprotection in other apoptotic paradigms is under investigation and appears to involve activation of the Rap-1/B-Raf module and/or the PI3-K/Akt survival pathway.
The contribution of immunomodulatory molecules produced by astrocytes and/or microglia towards neuroprotection by ICP10PK is a newly developed topic of interest in the laboratory. We have constructed a growth defective HSV-2 vector for delivery of ICP10PK, and are using it to study neuroprotection in organotypic hippocampal cultures and mouse models of stroke and epilepsy.
Publications:
Li B, Smith CC, Laing JM, Gober MD, Liu L, Aurelian L. Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1.Oncogene. 2006 Dec 18; [Epub ahead of print] PMID: 17173073 [PubMed - as supplied by publisher]
Golembewski EK, Wales SQ, Aurelian L, Yarowsky PJ. The HSV-2 protein ICP10PK prevents neuronal apoptosis and loss of function in an in vivo model of neurodegeneration associated with glutamate excitotoxicity. Exp Neurol. 2007 Feb;203(2):381-93. Epub 2006 Oct 16. PMID: 17046754 [PubMed - in process]
Sharma BK, Smith CC, Laing JM, Rucker DA, Burnett JW, Aurelian L. Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions. Dermatology. 2006;213(3):192-9. PMID: 17033167 [PubMed - indexed for MEDLINE]
Gober MD, Laing JM, Thompson SM, Aurelian L. The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures. Brain Res. 2006 Nov 13;1119(1):26-39. Epub 2006 Oct 3. PMID: 17020750 [PubMed - indexed for MEDLINE]
Laing JM, Gober MD, Golembewski EK, Thompson SM, Gyure KA, Yarowsky PJ, Aurelian L. Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice. Mol Ther. 2006 May;13(5):870-81. Epub 2006 Feb 24. PMID: 16500153 [PubMed - indexed for MEDLINE]
Wales, S., Smith C.C. and Aurelian, L. The herpes simplex virus type 2 (HSV-2) gene ICP10PK has a wide neuroprotective spectrum through activation of survival signaling pathways. Revista Brasileira de Neurologia pp 113-126, 2006.
Wales, S.Q. and Aurelian, L. Neuroprotection by the herpes simplex virus type 2 protein ICP10PK Following loss of trophic growth support signaling molecules and survival pathways. J. Neurochem. Submitted.
