Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
Raymond P. Roos, MD
Marjorie and Robert E. Straus Professor in Neurological Science
eRA COMMONS USER NAME (credential, e.g., agency login)
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)
INSTITUTION AND LOCATION
FIELD OF STUDY
Columbia College, New York, NY
SUNY, Downstate Medical Center, NY
NINDS (Slow Virus Lab), NIH
Johns Hopkins Hospital, MD
Johns Hopkins Hospital, MD
Neurology residency Neuroimmunology/Neurovirology
A. Personal Statement: The goal of the present proposal is to clarify the pathogenesis of familial amyotrophic lateral sclerosis (FALS). We will focus on mutant SOD1-induced FALS, and use transgenic mice as models for this disease. Our studies will investigate the importance of ER stress, the UPR, and oxidative stress. Goals of this proposal are to clarify the pathogenesis of ALS and identify new directions for treatment. I have worked in the field of ALS for over two decades. It was on my NIH-funded Program Project that the first linkage was made in FALS (which turned out to be linkage to the SOD1 gene). My lab has extensive experience with both in vitro as well as transgenic mouse studies in FALS. We were the first investigators to use intramuscular injections of viral vectors in order to deliver genes to motor neurons. I have served on groups reviewing ALS grants, including chairing an ALS Association Scientific Review Committee. In 2004, I received the Donald W. Mulder award, which is given by the ALS Association to “ individuals who exemplify the traits of leadership, dedication, and achievement in combating ALS”. I served as Chairman of the Department of Neurology at the University of Chicago for ~8 years.
B. Positions: 1976-1982: Asst Prof of Neurology, Univ Chicago, Chicago, IL;
1977-present: Member, Comm of Virology (now called Comm of Microbiology), Univ Chicago; 1980-1981: Res Assoc, Visiting Prof, Dept Cellular, Viral and Molec Biol, Univ Utah, Salt Lake City, Utah;
1982-1986: Assoc Prof, Dept Neurology, Univ Chicago;
1988-1989: Visiting Scientist, Dept. Microbiol and Molec Genet, UC Irvine, CA;
1986-2001: Prof of Neurology, Univ Chicago; Chairman of Neurology (‘96-‘04), Univ Chicago; 2001-present: Marjorie and Robert E. Straus Professor in Neurological Science, Dept Neurology; Member, Comm of Immunology, Comm of Neurobiol, Univ Chicago
: 1990-1994: NINCDS Program Project Review Comm Study Section
1992-1995: Vaccines and Related Biological Products Advisory Comm, U.S. F.D.A. (Chair–‘95) 1994-2001: Editorial Boards: J Neuroimmunol, J Neurovirol
1996-2000: NIH Virology Study Section
1996-2000: Transmissible Spongiform Encephalopathies U.S. F.D.A. Advisory Comm;
1975-1978: Scientific Review Comm, ALS Assn
1999-2000: The National Academy of Sciences Institute of Medicine Committee to Examine “Multiple Sclerosis; Current Status and Strategies for the Future”
2000-2001: Chairman, Scientific Review Comm, ALS Assn
2001-present: Senior Assoc Ed, MedLink
2002-2003: The National Academy of Sciences Institute of Medicine Comm to Examine Prion Research and Policy
2002-2009: National Multiple Sclerosis Society Research Programs Advisory Comm (2007-2009 – Chair); Amer Acad of Neurol Science Comm; Editorial Board: Ann Neurol
2004-2007: Scientific Review Comm, ALS Assn
2004: AAAS Fellow in Medical Science (For studies on the mechanisms of degenerative diseases in viral and non-viral diseases, particularly for studies of picornavirus central nervous system infections); Donald W. Mulder award (given by the ALS Association)
2005: Fellow in Medical Sciences, AAAS
2005-present: Editorial Board, J Virol
2006:Member, Johns Hopkins Society of Scholars
C. Selected Peer-reviewed Publications
(from over 140 peer-reviewed publications) most relevant to the current application:
Siddique, T., Figlewicz, D.A., Pericak-Vance, MA., Haines, J.L., Rouleau, G., Jeffers A.J., Sapp, P., Roos, R.P., et al.: Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence for genetic locus heterogeneity. New Engl. J. Med. 324:1381-1384, 1991.
Deng, H.-X., Hentati, A., Tainer, J.A., Cayabyab, A., Hung, W.-Y., Getzoff, E.D., Herzfeldt, B., Roos, R.P., Warner, C., Deng, G., Soriano, E., Smyth, C., Parge, H.E., Ahmed, A., Roses, A.D., Hallewell, R.A., Pericak-Vance, M.A., and Siddique, T. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261:1047-1057, 1993.
Roos, R.P., Ghadge, G.D., Kang, U.J., Wollman, R., Fishman, P.S., Kalynych, A.M., Barr, E., and Leiden, J.M. CNS gene delivery by retrograde transport of recombinant replication-defective adenoviruses. Gene Therapy 2: 132-137, 1995.
Roos, R.P., Siddique, T., and Tainer, J.A., Summary of "Superoxide Dismutase (SOD) and Free Radicals in Amyotrophic Lateral Sclerosis and Neurodegeneration" Conference. Neurology 45:1779-1780, 1995.
Jordan, J., Ghadge, G.D., Prehn, J.H.M., Bindokas, V.P., Toth, P.T., Roos, R.P., and Miller, R.J. Expression of human Cu/Zn superoxide dismutase inhibits the death of rat sympathetic neurons caused by withdrawal of nerve growth factor. Molec. Pharm.47:1095-1100, 1995.
Ghadge, G.D.*, Lee, J.P.*, Bindokas, B.P., Jordan, J., Ma, L., Miller, R.J., Roos, R.P. Mutant superoxide dismutase-1-linked FALS: Molecular mechanisms of neuronal death and protection. J. Neurosci. 17(22):8756-8766, 1997.
Lee, J., Palfrey, C., Bindokas, V.P., Ghadge, G.D., Miller, R.J., and Roos, R.P. The role of immunophilins in mutant superoxide dismutase-1-linked FALS (familial amyotrophic lateral sclerosis). Proc. Natl. Acad. Sci. 96:3251-3256, 1999.
Ghadge, G.D., Slusher, B.S., Bodner, A., Dal Canto, M.,Wozniak, K., Thomas, A., Rojas, C., Tsukamoto, T., Majer, P., Miller, R.J., Monti, A.L., and Roos, R.P. Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial ALS (FALS) models. Proc. Natl. Acad. Sci. 100:9554-9559, 2003.
Ghadge, G.D., Wang, L., Sharma, K., Monti, A.L., Bindokas, V., Stevens, F.J., Roos, R.P. Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord. Neurobiol. Dis. 2:194-205, 2006.
Wang, L., Sharma, K., Deng, H.-X., Siddique, T., Grisotti, G., Liu, E., Roos, R.P. Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology. Neurobiol. Dis. 29: 400-408, 2008.
Wang, L., Deng, H.-X., Grisotti, G., Zhai, H., Siddique, T., Roos, R.P. Wild type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse. Hum Mol Genet 18:1642-1651, 2009. PMCID: PMC2667291
Wang, L., Sharma, K., Grisotti, G., Roos, R.P. The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis, 35:234-240, 2009. PMCID: PMC2706919
Wang, L., Grisotti, G., Roos, R.P. Mutant SOD1 knockdown in all cell types ameliorates disease in G85R SOD1 mice with a limited additional effect over knockdown restricted to motor neurons. J. Neurochem. 113: 166-174, 2010.
Wang, L., Gutmann, D.H.., Roos, R.P. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum Mol Genet 20:286-293, 2010.
Wang, L., Popko, B., Roos, R.P. The unfolded response in amyotrophic lateral sclerosis. Hum Mol Genet 20:1008-1015, 2011.
D. Ongoing Research Support
– No overlap with present proposal
Project Number: 1R21NS067341-01 (co-PIs: Roos and Kay) 09/30/2009 – 08/31/2011
Title: Phage Display Investigations of TDP-43
Specific Aims: Identify and characterize peptides that bind TDP-43 and predict the cellular interacting proteins. Identify and characterize single chain fragments of variable region antibodies (scFvs) that can be used to clarify the function of TDP-43 and may have therapeutic potential.
Project Number: 1 R21 NS066175-01A1 (Roos) 04/01/10 - 03/31/12
Title: Single chain Fragments of variable regions in the treatment of Familial ALS
Goal: Prepare and characterize scFvs directed against wild type and mutant SOD1.
Project Number: (PI – Soliven, co-I - Roos) 05/1/09 - 04/30/11
Agency: NIH/NIAID/Duke University Medical Center
Title: B cell Repertoire in Myasthenia Gravis
Specific Aims: To determine the antigenic target and B cell repertoire in myasthenia gravis.
Project Number: NA (Roos) 10/1/10-9/30/11 .
Title: Non-cell autonomous degeneration in FALS
Agency: ALS Association
Goal: To characterize non-cell autonomous degeneration in familial ALS
Project Number: 5 R25 NS065744-02 (Roos) 03/03/2009 - 02/28/2014
Title: Training grant
Goal: Preparing trainees in Neurology and Neurosurgery for academic research centers
Project Number: Pilot grant PP1640 (Roos) 3/01/2011- 2/29/2012
Title: Saffold virus and demyelination disease
Agency: National Multiple Sclerosis Society
Goal: Investigate the pathogenesis of SAFV diseases in an experimental mouse model; Develop and evaluate a reliable, highly sensitive RT-PCR assay to detect SAFV genome in CNS tissue from patients with MS
Completed research support over the last 3 years relevant to the present application
Project Number: None (Roos) 01/01/2008 - 12/31/2009
Title: Non-Cell Autonomous Degeneration in Familial ALS
Agency: The Les Turner ALS Foundation
Goal: Investigate non-cell autonomous degeneration in familial ALS.
Specific Aims: To determine whether G85R mutant SOD1 expression in motor neurons, microglia, Schwann cells, and oligodendrocytes contributes to the pathogenesis of MND in mice.
Project Number: 1749 (Roos) 08/01/2008 - 07/31/2010
Agency: The ALS Association
Title: Non-autonomous degeneration in FALS
Specific Aims: To determine whether G85R mutant SOD1 expression in astrocytes, Schwann cells and endothelial cells contributes to the pathogenesis of MND in mice.
Project Number: MDA4346 (Roos) 07/01/2007 - 06/30/2010
Agency: Muscular Dystrophy Association
Title: Transgenic mouse studies and therapeutic directions in ALS
Specific Aims: To explore the role of the UPR in FALS.