Annual Report 2011 - Center for Advanced Biotechnology and ...

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In the prior year, we have made considerable progress investigating late infantile neuronal ceroid lipofuscinosis (LINCL), a recessive neurodenerative disease of childhood that is due to deficiencies in the lysosomal protease tripeptidyl-peptidase 1 (TPP1). In one study, we performed mass spectrometric analyses on storage material and lysosomal fractions from an LINCL mouse model. This revealed several candidates for proteins stored in brain. In depth analysis of the most prominent of these, glial fibrillary acidic protein, revealed that this protein represented a contaminant that adventitiously associated with storage material and lysosomes during the isolation procedure. We also used the mouse model to explore potential therapeutic approaches and found that intrathecal administration of recombinant human TPP1 resulted in significant delivery of enzyme to the brain. Importantly, this treatment prolonged lifespan and improved decreased disease symptoms. Finally, in collaboration with scientists at the University of Missouri and BioMarin Therapeutics, as a step towards the clinic we conducted pilot enzyme replacement studies using an LINCL dog model. We are also continuing our investigation of the lysosomal proteome. Following the principles of de Duve and colleagues that lead to the discovery of the lysosome, we analyzed rat liver subcellular fractions using mass spectrometry to identify and determine the distribution of different proteins. This led to the identification of numerous candidate lysosomal proteins and provided further evidence that ABCB6 is lysosomal and that superoxide dismutase 1 has a mixed cytoplasmic-lysosomal localization. Percent survival 100 50 0 1.2 mg/animal 0.38 mg/animal 0.12 mg/animal 0.038 mg/animal vehicle 0 30 60 90 120 150 180 Time (days) Acute intrathecal administration of recombinant human TPP1 extends lifespan of a LINCL mouse model. Animals were administered the indicated dose of TPP1 at the age of 28-30 days and then followed for survival. Jennifer Wiseman Research Teaching Spec. Caifeng Zhao Research Teaching Spec. 23
Publications: Della Valle, M. C., Sleat, D. E., Zheng, H., Moore, D. F., Jadot, M. and Lobel, P. Classification of subcellular location by comparative proteomic analysis of native and density-shifted lysosomes. Mol.Cell. Proteomics. 2011 10, M110 006403. Qian, Y., Lee, I., Lee, W. S., Qian, M., Kudo, M., Canfield, W. M., Lobel, P. and Kornfeld, S. Functions of the alpha, beta, and gamma subunits of UDP- GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. J. Biol. Chem. 2010 285: 3360-3370. Vuillemenot, B. R., Katz, M. L., Coates, J. R., Kennedy, D., Tiger, P., Kanazono, S., Lobel, P., Sohar, I., Xu, S., Cahayag, R., Keve, S., Koren, E., Bunting, S., Tsuruda, L. S. and O'Neill, C. A. Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. Mol. Genet. Metab. 2011 104: 325-337. Xu, S., Sleat, D. E., Jadot, M. and Lobel, P. Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material. Biochem. J. 2010 428: 355-362. Xu, S., Wang, L., El-Banna, M., Sohar, I., Sleat, D. E. and Lobel, P. Large-volume intrathecal enzyme delivery increases survival of a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther. 2011 19: 1842-1848 24
Page 1: CENTER FOR ADVANCED BIOTECHNOLOGY A
Page 4 and 5: Director’s Overview CABM—25 and
Page 6 and 7: of Health, National Science Foundat
Page 8 and 9: Cell & Developmental Biology Labora
Page 10 and 11: protein metabolism/activity, such t
Page 12 and 13: Dr. Céline Gélinas CABM Resident
Page 14 and 15: (CHINJ, CINJ and CABM) and Lauri Go
Page 16 and 17: Dr. Masayori Inouye CABM Resident F
Page 18 and 19: Xu, Z., Mirochnitchenko, O., Xu, C.
Page 20 and 21: Dr. Fang Liu CABM Resident Faculty
Page 22 and 23: Publications: Matsuura, I., Chiang,
Page 26 and 27: Dr. James Millonig CABM Resident Fa
Page 28 and 29: We have mapped 5 different vl modif
Page 30 and 31: Dr. Arnold Rabson Director Child He
Page 32 and 33: Publications: Zheng, X., Cui, X.X.,
Page 34 and 35: polymerase II, facilitating the sel
Page 36 and 37: Dr. Mengqing Xiang CABM Resident Fa
Page 38 and 39: neurons diminish while there is a s
Page 40 and 41: Laboratory Faculty Director Structu
Page 42 and 43: Human transcription factors are typ
Page 44 and 45: atomic detail and have yielded nume
Page 46 and 47: Figure from Das et al., 2011 showin
Page 48 and 49: Dr. Helen M. Berman Board of Govern
Page 50 and 51: Dr. Chenghua Shao Research Associat
Page 52 and 53: Dr. Joseph Marcotrigiano CABM Resid
Page 54 and 55: The long-term goals of our studies
Page 56 and 57: s Publications: Singarapu, K.K., Mi
Page 58 and 59: Zhao, L., Zhao, K., Hurst, R., Slat
Page 60 and 61: Acton, T.B., Xiao, R., Anderson, S.
Page 62 and 63: Kryshtafovych, A., Bartual, S.G., B
Page 64 and 65: properties by lowering susceptibili
Page 66 and 67: Dr. Ann M. Stock Associate Director
Page 68 and 69: Publications: Barbieri, C.M., Mack,
Page 70 and 71: Lectures and Seminars 69
Page 72 and 73: CABM RETREAT, June 30, 2011 Cook Ca
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25 th Anniversary CABM Symposium Fr
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Edery Lab Joseph Albistur George Gh
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PATENTS P. Lobel, et al. “Methods
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Montelione, G.T., Ma, L. and Krug,
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Outside Academic Members Dr. Wayne
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Former CABM Scientific Advisory Boa
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Fiscal Information 86
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Anderson, Stephen Rutgers CABM Gran
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Leukemia & Lymphoma Society BFL-1 a
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Total Award Start - End FY 2011 Dir
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Department of Defense Tumor suppres
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Total Award Start - End FY 2011 Dir
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