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About Sickkids
About SickKids

Jim Hu, PhD

Research Institute
Senior Scientist
Translational Medicine

University of Toronto
Professor
Department of Laboratory Medicine and Pathobiology, Paediatrics


Phone: 416-813-6412
Fax: 416-813-5771
Email: jim.hu@sickkids.ca
Alternate Contact: University of Toronto
Alternate Email: jim.hu@utoronto.ca

Brief Biography

Dr. Jim Hu is presently a Senior Scientist in the Translational Medicine Program at 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
  • airway immune response

Research Activities

Development of gene therapy for airway genetic diseases

Current molecular biology and genetics technologies give us unprecedented means to identify the genetic mutations that cause diseases, to develop diagnostic methods, and to understand disease mechanisms. Research advancements have also enhanced the development of gene-based therapies for genetic lung diseases, such as cystic fibrosis (CF). Gene therapy works by replacing a gene carrying a disease-causing mutation with a healthy, functioning copy of the gene. Gene therapy has several advantages over conventional drug treatments or surgery; most importantly, it fixes the cause of a disease, not just the symptoms. Gene therapy is designed as a non-invasive treatment for infrequent use, thus reducing the drug and treatment burden on patients and improving their quality of life. Ultimately, gene therapy treatments will also be more cost-effective, reducing the financial burden on our healthcare system. Moreover, some drugs are only effective for certain gene mutations. By using a gene therapy approach, a single treatment would be able to help all patients with different mutations in the same disease-associated gene. My group has previously demonstrated that genes can be efficiently delivered to the lungs of mice, rabbits, and pigs. These technological advancements create a unique opportunity to treat lung genetic diseases like CF, by replacing disease-associated genes in the lung stem cells, which we are now directly targeting for long-term therapeutic gene expression. Discoveries made from our research will represent a major step forward in treating patients with genetic diseases of the lung, efficiently and cost-effectively.

Airway gene regulation

Many respiratory diseases, such as cystic fibrosis and asthma, involve pathological changes in lung epithelial cells. Therefore, understanding gene regulation in the lung epithelial cells has important health implications. We have been working on a set of epithelium-specific Ets-like transcription factor genes, ESE-1, ESE-2 and ESE-3, where the expression of ESE-1, in particular, is highly induced under inflammatory conditions. Using a knockout mouse model, we have shown that this gene is involved in regulating airway immune responses. We are currently elucidating its role in regulation of inflammation in other human diseases, such as sepsis and rheumatoid arthritis.

External Funding

  • Canadian Institutes of Health Research
  • Cystic Fibrosis 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

Xia E., Zhang Y, Cao H, Li J, Duan R, Hu J (2019). TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy. Genes (Basel). 10(1). pii: E39

Xia E, Duan R, Shi F, Seigel KE, Grasemann H, Hu J (2018). Overcoming the Undesirable CRISPR-Cas9 Expression in Gene Correction. Mol Ther Nucleic Acids. 13:699-709

Gupta S, Lee CM, Wang JF, Parodo J, Jia SH, Hu J, Marshall JC (2018). Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation. J Leukoc Biol. 103(5):933-944

Cao H, Ouyang H, Grasemann H, Bartlett C, Du K, Duan R, Shi F, Estrada M, Seigel KE, Coates AL, Yeger H, Bear CE Gonska T, Moraes TJ, Hu J (2018). Transducing Airway Basal Cells with a Helper-Dependent Adenoviral Vector for Lung Gene Therapy. Hum Gene Ther. 29(6):643-652

Lee CM, Gupta S, Wang J, Johnson EM, Crofford LJ, Marshall JC, Kapoor M, Hu J (2016). Epithelium-specific Ets transcription factor-1 acts as a negative regulator of cyclooxygenase-2 in human rheumatoid arthritis synovial fibroblasts. Cell Biosci. 6:43

Lee CM, Wu J, Xia Y, Hu, J (2016). ESE-1 in early development: approaches for the future. Front Cell Dev Biol. 4:73

Cao H, Wu J, Duan C, Du K, Yeger H, Hu J (2016). Long-term expression of the human CFTR gene in mouse airway via helper-dependent adenoviral vector delivery and transient immunosuppression. Hum Gene Ther. 27(1):83-91

Ankathatti Munegowda M, Hu. J (2015). Transient blocking NK cell function with small molecule inhibitors for helper dependant adenoviral vector-mediated gene delivery. Cell Biosci. 5:29

Cao H, Ouyang H, Ip W, Du K, Duan H, Avolio J, Wu J, Duan C, Yeger H, Bear C, Gonska T, Hu J, Moraes T (2015). Testing gene therapy vectors in human primary nasal epithelial cultures. Mol Ther Methods Clin Dev. 2:15034

Lee CM, Gupta S, Parodo J, Wu J, Marshall JC, Hu J (2015). The uncovering of ESE-1 in human neutrophils: implication of its role in neutrophil function and survival. Genes Immun. 16(5):356-61

Yu Z, Xu J, Liu J, Wu J, Lee CM, Li Y, Hu J (2015). Epithelium-specific Ets-like transcription factor 1, ESE-1, regulates ICAM-1 expression in cultured lung epithelial cell lines. Mediators Inflamm, 2015:547928

Yan Z, Stewart ZA, Sinn PL, Olsen JC, Hu J, McCray Jr PB, Engelhardt JF (2015). Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy. Hum Gene Ther Clin Dev. 26(1):38-49

Xia E., Munegowda MA., Cao H, Hu J (2014). Lung gene therapy how to capture illumination from the light already present in the tunnel. Genes Dis. 1(1):40-52

Ren F, Wang R, Zhang Y, Liu C, Wang Y, Hu J, Zhang L, Chang Z (2014). Characterization of a monoclonal antibody against CREPT, a novel protein highly expressed in tumors. Monoclon Antib Immunodiagn Immunother. 33(6):401-8

Lam S, Cao H, Wu J, Duan R, Hu J (2014). Highly efficient retinal gene delivery with helper-dependent adenoviral vectors. Genes Dis. 1(2):227-237

Dhingra S, Wu J, Li SH, Guo J, Huang XP, Mihic A, Hu J, Weisel RD, Li RK (2014). Modulation of alloimmune responses by interleukin-10 prevents rejection of implanted allogeneic smooth muscle cells and restores postinfarction ventricular function. Cell Transplant. 24(6):1013-29

Cao H, Machuca TN, Yeung JC, Wu J, Du K, Duan R, Hashitomo K, Linacre V, Coates AL, Leung K, Wang J, Yeger H, Cutz H, Liu L, Keshavjee S, Hu J (2013). Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-dependent Adenoviral Vectors. Mol Ther Nucleic Acids. 2:e127

Guan R, EI-Rass S, Spillane D, Lam S, Wang Y, Wu J, Chen Z, Wang A, Jia Z, Keating A, Hu J, Wen YX (2013). rbm47, a Novel RNA Binding Protein, Regulates Zebrafish Head Development. Developmental Dynamics. Dev Dyn. 242(12):1395-404

Lee CM, Hu J (2013). Cell density during differentiation can alter the phenotype of bone marrow-derived macrophages. Cell Biosci. 3:30

Xia E, Hu J (2013). Advances in Cystic Fibrosis Gene Therapy. CML Cystic Fibrosis. 3(2):33-43

Lu D, Wu Y, Wang Y, Ren F, Wang D, Su F, Zhang Y, Yang X, Jin G, Hao X, He D, Zhai Y, Irwin DM, Hu J, Sung JJY, Yu J, Jia B, Chang Z (2012). CREPT Accelerates Tumorigenesis by Regulating the Transcription of Cell-Cycle-Related Genes. Cancer Cell. 21(1):92-104

Kushwah R, Oliver J, Duan R, Zhang L, Keshavjee S, Hu J (2012). Induction of immunological tolerance to adenoviral vectors by using a novel dendritic cell-based strategy. J. Virol. 86(7):3422-35

Cao H, Molday RS, Hu J (2011). Gene therapy: light is finally in the tunnel. Protein Cell. 2(12):973-89

Oliver JR, Kushwah R, Hu J (2011). Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease. Lab Invest. 92(3):320-30

Kushwah R, Oliver JR, Wu J, Chang Z, Hu J (2011). Elf3 Regulates Allergic Airway Inflammation by Controlling Dendritic Cell-Driven T Cell Differentiation. J Immunol. 187(9):4639-53

Kushwah R, Hu J (2011). Role of dendritic cells in the induction of regulatory T cells. Cell Biosci. 1(1):20

Oliver JR, Kushwah R, Wu J, Pan J, Cutz E, Yeger H, Waddell TK, Hu J (2011). Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury. Lab Invest. 91(10):1514-29

Wu L, Lam S, Cao H, Guan R, Duan R, van der Kooy D, Bremner R, Molday RS, Hu J (2011). Subretinal gene delivery using helper-dependent adenoviral vectors. Cell Biosci. 1(1):15

Kushwah R, Hu J (2011). Complexity of dendritic cell subsets and their function in the host immune system. Immunology. 133(4):409-19

Cao H, Wu J, Lam S, Duan R, Newnham C, Molday RS, Graziotto JJ, Pierce EA, Hu J (2011). Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8-implications in the pathogenesis of RP. PLoS One. 6(1):e15860

Zhou Z, Hu J, Passafaro M, Xie W, Jia Z (2011). GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. J Neurosci. 31(3):819-833

Hu J, Wan Y (2011). Tolerogenic dendritic cells and their potential applications. Immunology. 132(3):307-14

Ye L, Zhu W, Backx PH, Cortez MA, Wu J, Chow YH, McKerlie C, Wang A, Tsui LC, Gross GJ, Hu J (2010). Arrhythmia and sudden death associated with elevated cardiac chloride channel activity. J Cell Mol Med. 15(11)2307-16

Cao H, Yang T, Li XF, Wu J, Duan C, Coates AL, Hu J (2010). Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression. Gene Ther. 18(2):173-81

Lee BH, Kushwah R, Wu J, Ng P, Palaniyar N, Grinstein S, Philpott DJ, Hu J (2010). Adenoviral vectors stimulate innate immune responses in macrophages through cross-talk with epithelial cells. Immunol Lett. 134(1):93-102

Yang T, Duan R, Cao H, Lee BH, Xia C, Chang Z, Tanswell AK, Hu J (2010). Development of an inflammation-inducible gene expression system using helper-dependent adenoviral vectors. J Gene Med. 12(10):832-9

Kushwah J, Hu J (2010). Dendritic cell apoptosis: regulation of tolerance versus immunity. J. Immunol. 185 (2):795-820

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. 38(19):6684-96

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):361-72

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):7104-18

Oliver JR, Kushwah R, Wu J, Cutz E, Yeger H, Waddell TK, Hu J (2009). Gender differences in pulmonary regenerative response to naphthalene induced bronchiolar epithelial cell injury. Cell Prolif. 42(5):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):26456-65

Wong AP, Keating A, Lu WY, Duchesneau P, Wang X, Sacher A, Hu J, Waddell TK (2009). Identification of a bone marrow-derived epithelial-like population of repopulating injured mouse 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):208-15

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):225-39

Kushwah R, Cao H, Hu J. (2008). Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery. J. Immunol. 180(6):4098-108

Li J, Xiang YY, Ye L, Tsui LC, MacDonald JF, Hu J, Lu WY (2008). Nonsteroidal anti-inflammatory drugs upregulate function of wild-type and mutant CFTR. Eur Respir J. 32(2):334-43

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. 18(6):649-63

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):518-33

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. 27(37):4973-85

Kushwah R, Oliver JR, Cao H, Hu J (2007). Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways. Gene Ther. 14(16):1243-8

Wong AP, Dutly AE, Sacher A, Lee H, Hwang D, Liu MY, Keshavjee S, Hu J, Waddell TK (2007). Targeted cell replacement with bone marrow cells for airway epithelial regeneration. Am J Physiol Lung Cell Mol Physiol. 293(3):L740-52

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):16401-12

Kushwah R, Cao H, Hu J (2007). Potential of helper-dependent adenoviral vectors in modulating airway innate immunity. Cell Mol Immunol. 4(2):81-9

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):773-80

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 EW (2006). Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo. Respir Res. 7:26

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

Farmen SL, Karp PH, Ng P, Palmer DJ, Koehler DR, Hu J, Beaudet AL, Zabner J, Welsh MJ (2005). Gene transfer of CFTR to airway epithelia: low levels of expression are sufficient to correct CI-transport and overexpression can generate basolateral CFTR. Am J Physiol Lung Cell Mol Physiol. 289(6):L1123-30

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. 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. 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. 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. 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. 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). Am J Respir Cell Mol Biol. 31(4):377-81

Navab R, Gonzalez-Santos JM, Johnston MR, Liu J, Brodt P, Tsao M-S, Hu J (2004). Expression of chicken ovalbumin upstream promoter-transcription factor II enhances invasiveness of human lung carcinoma cells. Cancer Res. 64(15):5097-105

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 H460SM variant cell line reveals novel candidate genes for systemic metastasis. Oncogene. 23(37):6316-24

Cao H, Koehler DR, Hu J (2004). Adenoviral vectors for gene replacement therapy (invited review). Viral Immunol. 17(3):327-33

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(26): 15364-9

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. Mol Ther. 7(5 Pt 1):649-58

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. J Biol Chem. 277(26):23764-72

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. Am J Respir Cell Mol Biol. 27(3):273-85

Koehler DR, Hitt MM, Hu J (2001). Challenges and strategies for cystic fibrosis lung gene therapy. Mol Ther. 4(2):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. Mol Ther. 3(5 Pt 1):723-33

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. Mol Ther. 4(1):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. Mol Ther. 2(4):359-67

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. Pediatr Res. 48(2):184-90

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. Pediatr Res. 46(2):208-14

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(2):273-5

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(26):14695-700

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. Hum Mol Genet. 6(12):2117-26

Hu J, Xu D, Schappert K, Xu Y, Friesen JD (1995). Mutational analysis of Saccharomyces cerevisiae U4 snRNA identifies functionally important domains. Mol Cell Biol. 15(3):1274-85

Intellectual Property

Episomal Cassettes for Gene Therapy (WO 98/51807)