Brief Biography

Dr. Jim Hu is presently a Senior Scientist in the Physiology & Experimental Medicine Program at the Research Institute, The Hospital for Sick Children (SickKids). He is also a Professor in the Departments of Laboratory Medicine and Pathobiology and Paediatrics and is a member of the Graduate Faculty of the Institute of Medical Science, University of Toronto.

Dr. Hu received his PhD in Biology from Harvard University. His PhD studies on RNA polymerase and gene transcription were carried out under the supervision of Dr. Lawrence Bogorad in the Department of Cellular and Developmental Biology. After graduating, Dr. Hu came to SickKids for his postdoctoral training in RNA splicing with Dr. James D. Friesen in the Department of Genetics.

Dr. Hu serves as a member of the American Society of Gene Therapy Genetic Diseases Committee (2007-2010) and as a member of the Medical/Scientific Advisory Committee of the Canadian Cystic Fibrosis Foundation and Chair of its Research Subcommittee (2006-2009). He has also served several terms as a member of the CIHR Respiratory Committee.

Research Interests

• lung gene regulation
• lung gene therapy
• pre-mRNA splicing
• airway immune response
• retinitis pigmentosa
• cancer

Research Activities

The long-term research interests of my group are gene expression and gene therapy. We have several major ongoing projects:

Gene regulation in airway epithelia
Many respiratory diseases, such as cystic fibrosis and asthma, involve pathological changes in lung epithelial cells. Therefore, understanding gene regulation in lung epithelial cells has important health implications. We have investigated the DNA control elements of human epithelium-specific genes such as K18 and CC10 and developed various expression cassettes for gene expression analysis in cells and in mice. We have also been developing Tet-inducible systems for gene function analysis in mice airway. Currently, we have been working on a set of epithelium-specific Ets-like transcription factor genes, ESE-1, ESE-2 and ESE-3. These genes are interesting to us because of their potential disease implications.

Gene therapy
Gene therapy offers the prospect of treating the underlying cause of many serious diseases. Despite numerous clinical trials, gene therapy successes have been rare. The low efficiency of gene delivery and the lack of long term gene expression in target cells remain the major problems for gene therapy. My group has been taking two novel strategies to enhance the safety and efficiency of lung gene therapy vectors. Through utilization of transcription enhancers and introns from the human 18 gene, a novel epithelium-specific expression cassette was developed. Our second strategy is to combine our cell-specific gene expression cassette with a helper-dependent (gutted) adenoviral vector. We have demonstrated that this combination is very powerful and we can prevent CF mice from acute lung infection by B. cepacia by delivering such a vector expression human CFTR to mouse airway. We are using larger animals to confirm the utility of these vectors. We have also been developing novel viral vectors for retinal degenerative diseases.

RNA processing/Retinitis Pigmentosa
Retinitis Pigmentosa (RP) refers to a group of hereditary retinal dystrophies characterized by a progressive loss of vision. It currently affects more than 1.5 million individuals worldwide. Mutations in at least 36 genes are linked to RP although the mechanism underlying the disease process is not clear. Recently, mutations in three splicing factor genes were reported to cause RP. One of these genes, PRPF3, which encodes a human splicing factor, was first cloned and extensively studied in my laboratory. We are currently investigating how mutations in PRPF3 could lead to RP.

In addition to the above research projects, we have also been developing novel gene therapy approaches for cancer.

External Funding

• Canadian Institutes of Health Research
• Canadian Cystic Fibrosis Foundation
• Foundation Fighting Blindness-Canada

Achievements

• 1998-2000, Power of Dreams Research Award from Canadian Cystic Fibrosis Foundation
• 2000-2005, Canadian Cystic Fibrosis Foundation Scholarship
• 2004-2007, Premier’s Research Excellence Award of Ontario
• 2005-2006, Zellers Senior Scientist Award from Canadian Cystic Fibrosis Foundation

Publications

Kushwah J and Hu J (2010) Dendritic cell apoptosis: regulation of tolerance versus immunity, J. Immunol. 185 (2). link to upcoming article

Chen Z, Ma X, Zhang J, Hu J, Gorczynski RM.(2010) Alternative splicing of CD200 is regulated by an exonic splicing enhancer and SF2/ASF, Nucleic Acids Res. 2010 Jun 17.  [Epub ahead of print] PMID: 20558599

Newnham CM, Hall-Pogar T, Liang S, Wu J, Tian B, Hu J, Lutz CS. (2010) Alternative polyadenylation of MeCP2: influence of cis-acting elements and trans-acting factors. RNA Biol., 7(3).  [Epub ahead of print] PMID: 20400852

Kushwah R, Wu J, Oliver JR, Jiang G, Zhang J, Siminovitch KA, Hu J.(2010) Uptake of apoptotic DC converts immature DC into tolerogenic DC, which induce differentiation of Foxp3+ regulatory T cells. Eur J Immunol. 40(4):1022-1035

Kushwah R, Oliver JR, Zhang J, Siminovitch KA, Hu J. (2009) Apoptotic dendritic cells induce tolerance in mice through suppression of dendritic cell maturation and induction of antigen-specific regulatory T cells. J. Immunol. 183(11):7104-7118

Oliver JR, Kushwah R, Wu J, Cutz E, Yeger H, Waddell TK, Hu J. (2009) Gender differences in the pulmonary regenerative response to naphthalene induced bronchiolar epithelial cell injury. Cell Prolif. 42:672-687

Wang P, Wang Q, Sun J, Wu J, Li H, Zhang N, Huang Y, Su B, Li R, Liu L, Zhang Y, Elsholtz HP, Hu J, Gaisano HY, Jin T. (2009) POU homeodomain protein Oct-1 functions as a sensor for cyclic AMP. J. Biol. Chem. 284(39):26456-26465.

Wong AP, Keating A, Lu WY, Duchesneau P, Wang X, Sacher A, Hu J, Waddell TK. (2009) Identification of a novel epithelial-like bone marrow progenitor cell population that can repopulate the airway epithelium. J. Clin. Invest. 119(2):336-348

Rong Z, Wang A, Li Z, Ren Y, Cheng L, Li Y, Wang Y, Ren F, Zhang X, Hu J, Chang Z. (2009) IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling. Cell Res, 19(2):208-215.

Gonzalez-Santos JM, Cao H, Duan R, Hu, J. (2008), Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex. Hum Mol Genet.17(2):225-239.

Kushwah R, Cao H, Hu J. (2008), Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intra-nasal delivery. J. Immunol. 180:4098-4108.

Li J, Xiang YY, Ye L, Tsui LC, MacDonald JF, Hu J, Lu WY (2008), Non-steroidal anti-inflammatory drugs enhances the wild-type and delta-F508 mutant CFTR Eur. J. Respir. (PMID:18385167).

Wu J, Duan R., Cao H, Field D, Newnham CM, Koehler DR, Zamel N, Pritchard MA, Hertzog P, Post M, Tanswell A K, Hu J (2008), Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation. Cell Res. May 13. [Epub ahead of print] PMID: 18475289.

Ren Y, Cheng L, Rong Z, Li Z, Li Y, Zhang X, Xiong S, Hu J, Fu XY, Chang Z (2008), hSef potentiates EGF-mediated MAPK signaling through attenuating EGFR degradation. Cell Signal., 20(3):518-533.

Navab R, Pedraza C, Fallavollita L, Wang N, Chevet E, Auguste P, Jenna S, You Z, Bikfalvi A, Hu J, O'Connor R, Erickson A, Mort JS, Brodt P. (2008), Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels. Oncogene. 2008 May 12. [Epub ahead of print]PMID: 184

Kushwah R, Oliver JR, Cao H, Hu J (2007), Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways. Gene Ther 14(16):1243-1248.

Wong AP, Dutly AE, Sacher A, Lee H, Hwang D, Liu MY, Keshavjee S, Hu J, Waddell TK. (2007), Direct intratracheal delivery of bone marrow cells enhances engraftment in an acutely injured airway epithelium. AJP Lung Cell Mol Physiol [Epub ahead of print] PMID: 17616650

Xu J, Bai XH, Lodyga M, Han B, Xiao H, Keshavjee S, Hu J, Zhang H, Yang B, Liu M. (2007), XB130, a novel adaptor protein for signal transduction. J. Biol Chem 282(22):16401-16412.

Kushwah R, Cao H, Hu J. (2007), Potential of helper-dependent adenoviral vectors in modulating airway innate immunity. Cell Mol Immunol 4:81-89

Flotte TR, Ng P, Dylla DE, McCray PB Jr, Wang G, Kolls JK, Hu J. (2007), Viral vector-mediated and cell-based therapies for treatment of Cystic Fibrosis. Mol Ther. 15(2):229-41.

Chang Z, Babiuk LA, Hu J. (2007), Therapeutic and prophylactic potential of small interfering RNAs against severe acute respiratory syndrome: progress to date. BioDrugs. 21(1):9-15.

Koehler D, Martin B, Corey M, Palmer D, Ng P, Tanswell AK, Hu J. (2006), Readministration of helper-dependent adenovirus vectors to mouse lung. Gene Ther. 13(9):773-780

Griesenbach U, Kitson C, Garcia SE, Farley R, Singh C, Somerton L, Painter H, Smith RL, Gill DR, Hyde SC, Chow Y-H, Hu J, Gray M, Edbrooke M, Ogilvie V, MacGregor G, Scheule RK, Cheng S-H, Caplen NJ, Alton E W. (2006), Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo. Respir. Res. 2006 Feb 15;7:26. PMID: 16480492

Chang Z, Hu J. (2006), Can siRNAs conquer SARS? Gene Ther. 2006 Jun;13(11):871-2.

Farmen SL, Karp PH, Ng P, Koehler DR, Hu J, Beaudet AL, Zabner J, Welsh MJ. (2005), Transgene expression from helper-dependent adenovirus with the cytokeratin-18 promoter in differentiated human airway epithelia. Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1123-1130.

Lee H, Koehler DR, Pang CY, Levine RH, Ng P, Palmer DJ, Quinton PM, Hu J. (2005), Gene delivery to human sweat glands: a model for cystic fibrosis gene therapy. Gene Ther. 2005 Dec;12(24):1752-60.

Koehler DR, Frndova H, Leung K, Louca E, Palmer D, Ng P, McKerlie C, Cox P, Coates AL, Hu J. (2005), Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter. J Gene Med. 2005 Nov;7(11):1409-20.

Yaniw D, Hu J. (2005), Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1. Cell Res. Jun;15(6):423-9.

Gonzalez-Santos JM, Cao H, Wang A, Koehler DR, Martin B, Navab R, Hu J. (2005), A complementation method for functional analysis of mammalian genes. Nucleic Acids Res. Jun 8;33(10):e94.

Cao HB, Wang A, Martin B, Koehler DR, Zeitlin PL, Tanswell AK, Hu J. (2005), Down-regulation of IL-8 expression in human airway epithelial cells through helper-dependent adenoviral-mediated RNA interference. Cell Res. Feb;15(2):111-9

Koehler DR, Downey GP, Sweezey NB, Tanswell AK, Hu J. (2004), Lung inflammation as a therapeutic target in Cystic Fibrosis (invited review). The American Journal of Respiratory Cell and Molecular Biology, 31:377-381.

Navab R, Gonzalez-Santos JM, Johnston MR, Liu J, Brodt P, Tsao M-S, Hu J. (2004), Enhanced invasion of human lung carcinoma cells by COUP-TFII. Cancer Research 64:5097-5105

Liu J, Blackhall F, Seiden I, Jurisica I, Navab R, Liu N, Radulovich N, Wigle D, Sultan M, Pintilie M, Hu J, Tsao M-S, Johnston M. (2004), Modeling of lung cancer by an orthotopically growing NCI-H460SM metastatic variant cell line reveals novel candidate genes for systemic metastasis. Oncogene 23:6316-6324.

Cao H, Koehler DR, Hu J. (2004), Adenoviral vectors for gene therapy (invited review). Viral Immunology 17 (3):327-333.

Koehler DR, Sajjan U, Chow Y-H, Martin B, Kent G, Tanswell AK, McKerlie C, Forstner J, Hu J. (2003), Protection of Cftr Knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia. Proc. Natl. Acad. Sci. USA 100: 15364-15369.

Toietta G, Koehler DR, Finegold M, Lee B, Hu J, Beaudet AL. (2003), Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter. Molecular Therapy, Vol 7, No. 5:649-658.

Gonzalez-Santos JM, Wang A, Jones J, Ushida C, Liu J, Hu J. (2002), Central region of the human splicing factor Hprp3p interacts with Hprp4p. Journal of Biological Chemistry Vol 277:23764-23772.

Navab R, Wang Y, Chow Y-H, Wang A, Jankov RP, Takamoto N, Tsai SY, Tsai M-J, Tanswell AK., Hu J. (2002), Regulation of human CC10 expression by COUP-TFs. The American Journal of Respiratory Cell and Molecular Biology. 27:273-285.

Koehler DR, Hitt MM, Hu J. (2001), Challenges and strategies for cystic fibrosis lung gene therapy. Molecular Therapy, Vol. 4, No. 2, August; 84-91.

Ye L, Chan S, Chow Y-H, Tsui L-C, Hu J. (2001), Regulated expression of the human CFTR gene in epithelial cells. Molecular Therapy, Vol. 3, No. 5, May (part 1 of 2): 723-733.

Koehler DR, Hannam V, Belcastro R, Steer B, Wen Y, Post M, Downey G, Tanswell AK, Hu J. (2001), Targeting transgene expression for cystic fibrosis gene therapy. Molecular Therapy, Vol. 4, No. 1, July: 58-65

Chow Y-H, Plumb J, Wen Y, Steer B M., Lu Z, Buchwald M., Hu, J. (2000), Targeting transgene expression in tracheal submucosal glands, Prominent sites of Human CFTR expression. Molecular Therapy, 2:359-367.

Koehler DR, Chow Y-H., Plumb J, Wen Y, Rafii B, Belcastro R, Haardt M, Lukacs L, Post M., Tanswell AK, Hu J. (2000), A human epithelium-specific vector optimized in rat pneumocytes for lung gene therapy. Pediatric Research, 48:184-190.

Chow Y-H., O'Brodovich H, Plumb J, Wang Y, Hu, J. (1999), Hormonal Regulation and Genomic Structure of the Human Amiloride-sensitive Epithelial Sodium Channel alpha-subunit Gene. Pediatric Research, 46:208-214.

Heng HHQ, Wang A, Hu J. (1998), Mapping of the human HPRP3 and HPRP4 genes encoding U4-U6-associated splicing factors to chromosomes 1q21.1 and 9q31-q33. Genomics, 48: 273-275.

Chow Y-H, O'Brodovich H, Plumb J, Wen Y, Sohn K-J, Lu Z, Zhang F, Lukacs G, Tanswell AK, Hui CC, Buchwald M, Hu J. (1997), Development of an epithelium-specific expression cassette with human DNA regulatory elements for transgene expression in lung airways. Proc. Natl. Acad. Sci. USA 94: 14695-14700.

Wang A, Forman-Kay J, Luo Y, Luo M, Chow Y-H, Plumb J, Friesen JD, Tsui L-C, Heng HHQ, Woolford JL Jr, Hu J. (1997), Identification and characterization of human genes encoding Hprp3p and Hprp4p, interacting components of the spliceosome. Human Molecular Genetics, 6: 2117-2126.

Hu J, Xu D, Schappert K, Xu Y, Friesen JD. (1995), Mutational analysis of Saccharomyces cerevisiae U4 snRNA identifies functionally important domains. Molecular and Cellular Biology, 15: 1274-1285.

Intellectual Property

Episomal Cassettes for Gene Therapy (WO 98/51807)