Dr. Hao Ding received his Bachelor of Medicine from the Shanghai Medical University, China (1987); and his Ph.D. degree on Molecular Biology from the University of Leuven, Belgium (1997). His post-doctoral training (between 1997 and 2004) was done in the labs of Drs. Andras Nagy and Abhijit Guha at the Samuel Lunenfeld Research Institute, Toronto. In 2004, he was awarded a Canada Research Chair and had established his research laboratory at the Department of Biochemistry and Medical Genetics, University of Manitoba and is currently an Associate Professor.
Mouse modeling of gene’s function
A. To transgenic dissect the role of PDGF-C during development
By searching for new Vascular Endothelial Growth Factor (VEGF) family members, Dr. Ding has cloned a new member of the PDGF family: PDGFC. Using mouse transgenic approaches, Dr. Ding's laboratory has demonstrated that PDGFC is an important PDGFRα ligand and plays an important role in mouse embryogenesis and in tumorigenesis (Nature Genetics, 2004). Because of his work, he received two major scientific awards: (1) the 2005 CIHR Maud Menten Young Investigator Award, and (2) the 2006 Boehringer Ingelheim Canadian Young Investigator Award in Biological Science (selected from 46 applicants across Canada).
In the last six years, in collaboration with several research groups across the world, they were able to further demonstrate that PDGF-C signaling is important for protecting neurons from apoptosis by regulating GSK3beta phosphorylation (J Exp Med, 2010). This signalling could also be important for the establishment of cerebral, retinal and heart vascularization (Am J Pathol, 2012; PNAS, 2014). More recently, they also found that PDGF-C signalling could interact with PDGF-A pathway in multiple developmental processes, such as lung, heart and bone (Mol Cell Biol, 2013).
In 2014, in collaboration with Dr. Xuri Li at Zhongshan Ophthalmic Center, they had also reported that PDGF-C is a potent vascular protective and survival factor (PNAS, 2014). Importantly, they found that treatment with PDGF-C not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression, but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. All of these studies have led to a better understanding of the role of PDGF-C during development.
B. To transgenic dissect the role of RTEL1 DNA helicase in the maintenance of genomic stability
Dr. Ding has identified that a DNA helicase protein, termed RTEL1 (Regulator of Telomere Length 1), to be essential for the maintenance of telomeres and genomic stability (Cell, 2004). This work has advanced his laboratory’s understanding of telomere maintenance during normal development and tumorigenesis. To further understand the role of RTEL1, Dr. Ding’s laboratory has also generated several transgenic mouse models, such as conditional knockout (Genesis, 2007), knock-in (Science, 2013) and transgenic over-expressing of RTEL1 (Transgenic Res, 2012). With these genetic tools, in collaboration with Dr. Simon Boulton’s group at London Research Institute, they had identified the molecular mechanisms of RTEL1 in the maintenance of telomeres, i.e. to dissemble T-loop and G-quadruplex structures during telomere replication (Cell, 2012). These findings have provided a new knowledge about how telomeres are maintained and how telomere dysfunction can lead to genomic instability in cells. More recently, his laboratory has also applied a biochemical approach to identify a specific interaction of RTEL1 with PCNA (which acts as a core factor in DNA replication machinery). To further characterize this interaction, his laboratory has generated a knock-in mouse model to specifically disrupt RTEL1/PCNA interaction in vivo. In collaboration with Dr. Boulton's group, they have demonstrated that RTEL1/PCNA interaction is essential for DNA replication during mouse development. This function of RTEL1 is also required for the maintenance of genomic stability (Science, 2013). These findings not only expand their understanding of DNA replication, but also lead to identify a new molecular mechanism of RTEL1 in the maintenance of telomeres and genomic stability.
C. Mouse modeling of human genetic diseases
The mouse is an ideal organism for modeling human genetic diseases. Not only is the mouse genome more than 90% identical to the human genome, but mice are also physiologically similar to humans. In the last six years, his laboratory has generated several mouse models to investigate two human genetic diseases for which the putative disease-causing genes have been identified. In collaboration with Dr. Klaus Wrogemann, Department of Biochemistry and Medical Genetics, they have generated a TRIM32 knockout mouse model to confirm that TRIM32 mutation (identified by Dr. Wrogemann) is a causative factor for human Limb-girdle muscular dystrophy type 2H (LGMD2H) (Plos One 2012). In this study, they have also demonstrated that TRIM32 is essential for the regulation of muscle stem cells, implicating that dysfunctional muscle stem cells caused by loss of TRIM32 function could contribute to the development of LGMD2H. In addition, in collaboration with Dr. Barb Triggs-Raine, (also in the Department of Biochemistry and Medical Genetics) Dr. Ding’s laboratory has created EMG1 knockout and knock-in models, which not only uncovered the role of EMG1 in mouse pre-implantation embryo development (BMC Development Biology, 2009), but also revealed the pathogenesis of EMG1 mutation in the development of human Bardet-Biedl syndrome (BBA-Molecular Basis of Disease, 2015).
Vannier, J.B., Sandhu, S., Petalcorin, M., Wu, X., Nabi, Z., Ding, H*., Boulton, S.J*. RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication. Science, 2013, 342(6155):239-242
*shared corresponding authorship
Vannier, J.B., Pavicic-Kaltenbrunner, V., Petalcorin, M., Ding, H., Boulton, S.J. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell, 2012, 149 (4):795-806
Nicklas, S., Otto, A., Wu, X., Miller, P., Stelzer, S., Wen, Y., Kung, S., Wrogemann, K., Patel, K., Ding, H*., Schwamborn, J.C*. TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration. Plos One, 2012, 7(1):e30445
*shared corresponding authorship
Wu, X., Sandhu, S., Nabi, Z., Ding, H. Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis. Transgenic Res., 2012, 5:1109-1115
Sandhu, S., Wu, X., Nabi, Z., Rastegar, M., Kung, S., Mai, S., Ding, H. Loss of HLTF promotes intestinal carcinogenesis. Mol Cancer, 2012, 11:18
Cancer Research Society operating grant
Project: Function of RTEL1 in protecting cerebellar stem cells from medulloblastoma formation ($120,000)
Until June 30, 2017
BI new investigator award ($60,000)