Dr. Rajesh Miranda

Associate Professor

Research Interests

I am interested in the regulation of transitions between cell proliferation, cell suicide and differentiation in the developing central nervous system. Specifically, my research is focused on the mechanisms of estrogen action in the developing cerebral cortex. The estrogen receptor is expressed transiently during the differentiation of the cerebral cortex. We had previously found that there were significant reciprocal regulatory interactions between estrogen and the neurotrophin family of growth factors, in adult neurotrophin targets as well as during periods of neural differentiation. Since the neurotrophins are known to protect against cell suicide in a variety of tissues, we are currently examining whether estrogen and estrogen-neurotrophin interactions can regulate cell suicide in the developing cerebral cortex.

Using a conditionally immortalized cortical cell line that we have developed, we found that both estrogen and the neurotrophins prevent apoptotic cell death. However, estrogen but not the neurotrophins, also promote cell proliferation, suggesting both overlapping and distinct roles for estrogen in the developing cortex.

We are also examining the role of estrogen and the neurotrophins in the regulation of the cell death receptor Fas/Apo-1 in the developing cerebral cortex. Fas/Apo-1 is a member of the tumor necrosis factor receptor/pan-neurotrophin receptor family. Our research suggests that Fas/Apo-1 mRNA and protein are transiently expressed in neurons, glia and neuroblasts of the cerebral cortex during the peak period of apoptosis. Fas-L appears to be expressed in by cells in close proximity to Fas expressing cells. In an explant culture model, we found that estrogen and one neurotrophin (NT-3) specifically regulated the expression of Fas mRNA.

Thus my main research focus deals with how estrogen and estrogen-neurotrophin interactions may regulate cell suicide and cell cycle in the developing cerebral cortex. However, I am developing additional interests that revolve around the phenomenon of cell suicide. One of my collaborations examines the role of neurotropic viruses such as Theiler's murine enecphalo-myelitis virus in demyelination and cell suicide in the central nervous system. I am also interested in the role of neurotrophic factors in cell death associated with the fetal alcohol syndrome.

Education

Ph.D. in Biopsychology/Neurobiology, University of Rochester, 1989

Post doc, Columbia University, 1998-1994

Representative Publications

Miranda R., Ceckler T., Guillet R., Kellogg C.K., (1990) Early developmental exposure to benzodiazepine ligands alters brain 31P-NMR spectra in young adult rats. Brain Research, 506, 85-92.

Miranda R., Ceckler T., Guillet R., Kellogg C.K. (1990) Aging-related changes in brain metabolism are altered by prenatal exposure to diazepam. Neurobiology of Aging, 11, 117-122.

Toran-Allerand C.D., Bentham W., Miranda R., Anderson J.P. (1991) Insulin influences astroglial morphology and glial fibrillary acidic protein (GFAP) expression in organotypic cultures. Brain Research, 558, 296-304.

Toran-Allerand C.D., Miranda R., Hochberg R.B., MacLusky N.J. (1992) Cellular variations in estrogen receptor mRNA translation in the developing brain: evidence from combined 125I-estrogen autoradiography and non-isotopic in situ hybridization histochemistry. Brain Research, 576, 25-41.

Miranda R., Toran-Allerand C.D., (1992) Developmental regulation of estrogen receptor mRNA in the rat cerebral cortex: a non-isotopic in situ hybridization histochemistry study. Cerebral Cortex, 2, 1-15.

Toran-Allerand C.D., Miranda R., Bentham W., Sohrabji F., Brown T.J., Hochberg R.B., MacLusky N.J. (1992) Estrogen receptors co-localize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc. Natl. Acad. Sci. USA. 89, 4668-4672.

Miranda R., Sohrabji F., Toran-Allerand C.D. (1993) Neuronal colocalization of mRNAs for the neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions. Proc. Natl. Acad. Sci. USA. 90, 6439-6443.

Miranda R., Sohrabji F., Toran-Allerand C.D. (1993) Presumptive estrogen target neurons express mRNAs for both the neurotrophins and neurotrophin receptors: a basis for potential developmental interactions of estrogen with the neurotrophins. Molecular and Cellular Neurosciences, 4, 510-525.

Sohrabji F., Miranda R., Toran-Allerand C.D. (1994) Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. Journal of Neuroscience, 14, 459-471.

Sohrabji F., Greene L.A., Miranda R., Toran-Allerand C.D. (1994) Reciprocal regulation of estrogen and NGF receptors by their ligands in PC12 cells. Journal of Neurobiology 25, 974-988.

Miranda R., Sohrabji F., Toran-Allerand D. (1994) Interactions of estrogen with the neurotrophins and their receptors during neural development. Hormones and Behavior 28, 367-375.

Donovan M.J., Miranda R., Kraemer R., McCaffrey T., Tessarollo L., Mahadeo D., Sharif S., Kaplan D., Tsoulfas P., Parada L., Toran-Allerand D., Hajjar D.P., Hempstead B.L. (1995) Neurotrophin and neurotrophin receptors in vascular smooth muscle cells: Regulation in response to injury. American Journal of Pathology 147, 309-324.

Sohrabji, F., Miranda, R., Toran-Allerand, D. (1995) Identification of a putative estrogen response element in the gene encoding BDNF. Proc. Natl. Acad. Sci. USA 92, 11110-11114.

Miranda, R., Sohrabji, F., Singh, M.. Toran-Allerand, D. (1996) Nerve growth factor (NGF) regulation of estrogen receptors in explant cultures of the developing forebrain. Journal of Neurobiology 31, 77-87.

McAlhany Jr. R., West, J., Miranda, R. (1997) Glial-derived neurotrophic factor rescues calbindin-D28k-immunoreactive neurons in alcohol-treated cerebellar explant cultures. J. Neurobiology 33, 835-847.

Liang, F-Q., Sohrabji, F., Miranda, R., Earnest, B., Earnest, D. (1998) Expression of brain-derived neurotrophic factor and its cognate receptor, trkB, in the rat superchiasmatic nucleus. Experimental Neurology 151, 184-193.

Cheema, Z. F., Wade, S., Sata, M., Walsh, K., Sohrabji, F., Miranda, R.C., (1999) FAS/Apo [apoptosis]-1 and associated proteins in the differentiating cerebral cortex: induction of caspase-dependent cell death and activation of NF-kB. Journal of Neuroscience 19, 1754-1770.

Craig, J.C., Bennett, G.D., Miranda, R.C., Finnell, R.H. A potential role for Ribonucleotide Reductase subunit M1 gene expression in valproic acid-induced neural tube defects. (in press).

McAlhany, Jr. R.E, Miranda, R.C., Finnell, R.H., West, J.R., Alcohol decreases glial-derived neurotrophic factor (GDNF) release and alters GDNF-stimulated SHC phosphorylation without altering GDNF mRNA levels in the developing cerebellum. Alcoholism: Clinical and Experimental Research 23(10)m 1691-1697.

Wade, S., Oommen, P., Conner, W.C., Earnest, D., Miranda, R.C., (1999) Overlapping And Divergent Actions Of Estrogen And The Neurotrophins On Cell Fate and p53-Dependent Signal Transduction In Conditionally Immortalized Cerebral Cortical Neuroblasts. Journal of Neuroscience 19(16), 6994-7006.

McAlhany, Jr. R.E, Miranda, R.C., Finnell, R.H., West, J.R., (1999) Alcohol decreases glial-derived neurotrophic factor (GDNF) release and alters GDNF-stimulated SHC phosphorylation without altering GDNF mRNA levels in the developing cerebellum. Alcoholism: Clinical and Experimental Research 23(10), 1691-1697.

McAlhany, Jr. R.E., West, J.R., Miranda, R.C.(2000) Glial-derived neurotrophic factor (GDNF) prevents ethanol-induced apoptosis and jun kinase phosphorylation. Developmental Brain Research 119, 208-216.

Cheema, Z.F., West, J.R., Miranda, R.C. (2000) Ethanol induces Fas/Apo [apoptosis]-1 and cell suicide in the developing cerebral cortex.Alcoholism: Clinical and Experimental Research 24 (4), 535-543.

Anderson, R., Harting, E., Frey, M., Leibowitz, J.L., Miranda, R.C., (2000) A persistent (DA) strain of Theiler's murine encepahalomyelitis virus (TMEV) induces rapid necrosis as well as delayed apoptosis during the acute phase of infection of myelinated mouse cerebellar explant cultures. Brain Research 868 (2) 259-267.

Link to Vita

link to vita