UR Faculty: Howard J. Federoff

Ph.D. (1979) Albert Einstein College of Medicine M.D. (1983) Albert Einstein College of Medicine	Howard J. Federoff Professor of Neurology, Medicine, Microbiology & Immunology Director, Center for Aging and Developmental Biology Director, Neuroscience Graduate Program Primary Appointment: Neurology GEBS Cluster Affiliations: MOCB - Molecular Oncology and Cancer Biology MTEM - Molecular Toxicology and Environmental Medicine NS - Neuroscience
Research: Herpes virus vector development and gene therapy applications; elucidation of nerve growth factor function in the adult; study of environment and genetic interactions for Parkinson's disease; development of somatic mosaic mouse technologies
Contact Information: E-Mail: howard_federoff@urmc.rochester.edu
University of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 645 Rochester, New York 14642	Medical Center 1-9615 Phone: (585) 273-2190

Research Overview

Our long term interest is to understand the molecular mechanisms that underlie plasticity in the nervous system and to exploit these to predictably modify the intact and damaged nervous system. To this end we have developed several lines of investigation: 1) Development of herpes virus vectors to direct expression of therapeutic genes long term to different cellular compartments within the intact CNS. This project involves vector development with the goal of eliminating somatic cell extinction of transgene expression; 2) Elucidating the role of NGF in the adult hippocampus. A binary germline-somatic transgene system based on loxP/cre recombinase is being exploited to produce postnatal genetic mosaicism for NGF gain of function. Molecular, anatomic and behavioral assays are utilized to assess changes in the function of the NGF-responsive septohippocampal pathway; 3) Development of somatic mosaic mice to examine the syngergy between environmental neurotoxicants and specific neuronal vulnerability genes as a model for ParkinsonÕs disease. Somatic gain of gene function is produced by targeted cre recombinase delivery to generate the vulnerability state and followed by subsequent neurotoxicant exposure. Multiple levels of analyses are undertaken. 4) Modulation of sympathetic neural input by neurotrophic factor dysregulation. We have made transgenic animals to manipulate nerve growth factor (NGF) levels to dissect out its different functions in the developing and mature nervous system. Tissue specific constitutive expression of NGF results in sympathetic hyperinnervation of the expressing target organ and developmental perturbation of the neural crest contributions to that target organ.

Recent Publications

Reinblatt M, Pin RH, Federoff HJ, Fong Y. Utilizing tumor hypoxia to enhance oncolytic viral therapy in colorectal metastases. Ann Surg. 2004 Jun;239(6):892-9; discussion 899-902.

Arvanian VL, Bowers WJ, Petruska JC, Motin V, Manuzon H, Narrow WC, Federoff HJ, Mendell LM. Viral delivery of NR2D subunits reduces Mg2+ block of NMDA receptor and restores NT-3-induced potentiation of AMPA/kainate responses in maturing rat motoneurons. J Neurophysiol. 2004 May 19 [Epub ahead of print]

Ieda M, Fukuda K, Hisaka Y, Kimura K, Kawaguchi H, Fujita J, Shimoda K, Takeshita E, Okano H, Kurihara Y, Kurihara H, Ishida J, Fukamizu A, Federoff HJ, Ogawa S. Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. J Clin Invest. 2004 Mar;113(6):876-84.

Kyrkanides S, Miller JH, Bowers WJ, Federoff HJ. Transcriptional and posttranslational regulation of Cre recombinase by RU486 as the basis for an enhanced inducible expression system. Mol Ther. 2003 Nov;8(5):790-5.

Kyrkanides S, Miller JH, Federoff HJ. Systemic FIV vector administration: transduction of CNS immune cells and Purkinje neurons. Brain Res Mol Brain Res. 2003 Nov 6;119(1):1-9.

Harvey BK, Chang CF, Chiang YH, Bowers WJ, Morales M, Hoffer BJ, Wang Y, Federoff HJ. HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. Exp Neurol. 2003 Sep;183(1):47-55.

Zhang Y, Hong Y, Bounhar Y, Blacker M, Roucou X, Tounekti O, Vereker E, Bowers WJ, Federoff HJ, Goodyer CG, LeBlanc A. p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity. J Neurosci. 2003 Aug 13;23(19):7385-94.

Bowers WJ, Olschowka JA, Federoff HJ. Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy. Gene Ther. 2003 Jun;10(11):941-5. Review.

Wang X, Wiley RD, Evans TG, Bowers WJ, Federoff HJ, Dewhurst S. Cellular immune responses to helper-free HSV-1 amplicon particles encoding HIV-1 gp120 are enhanced by DNA priming. Vaccine. 2003 Jun 2;21(19-20):2288-97.

Olschowka JA, Bowers WJ, Hurley SD, Mastrangelo MA, Federoff HJ. Helper-free HSV-1 amplicons elicit a markedly less robust innate immune response in the CNS. Mol Ther. 2003 Feb;7(2):218-27.

Tolba KA, Bowers WJ, Muller J, Housekneckt V, Giuliano RE, Federoff HJ, Rosenblatt JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity. Cancer Res. 2002 Nov 15;62(22):6545-51.

Maguire-Zeiss KA, Bowers WJ, Federoff HJ. Somatic mosaic approaches and the aging brain. Neurobiol Aging. 2002 Sep-Oct;23(5):977-84. Review.

Bowers WJ, Federoff HJ. Amyloid immunotherapy-engendered CNS inflammation. Neurobiol Aging. 2002 Sep-Oct;23(5):675-6; discussion 683-4. Review.

Tolba KA, Bowers WJ, Eling DJ, Casey AE, Kipps TJ, Federoff HJ, Rosenblatt JD. HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia. Mol Ther. 2002 Oct;6(4):455-63.

Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002 Jul 12;297(5579):259-63.

Bowers WJ, Chen X, Guo H, Frisina DR, Federoff HJ, Frisina RD. Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea. Mol Ther. 2002 Jul;6(1):12-8.

Hocknell PK, Wiley RD, Wang X, Evans TG, Bowers WJ, Hanke T, Federoff HJ, Dewhurst S. Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responses. J Virol. 2002 Jun;76(11):5565-80.

Brooks AI, Stein CS, Hughes SM, Heth J, McCray PM Jr, Sauter SL, Johnston JC, Cory-Slechta DA, Federoff HJ, Davidson BL. Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6216-21.

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