Senior Lecturer in Biomedical / Vision Sciences
T: +44 (0)141 331 8763
Dr Shu graduated from Xiangya School of Medicine with PhD in Pathobiology (1999) and was then awarded a Wellcome Trust Travelling Fellowship to work in the University of Glasgow (1999-2001), where he worked on the human pathogen Paracoccidioides brasiliensis. From July 2001, he moved to MRC Human Genetics Unit, to work as an Investigator Scientist (2001-2005) then Senior Investigator Scientist, and his work is focused on the disease mechanisms of retinitis pigmentosa (RP) and age related macular degeneration (AMD). In February 2010 he joined the Department of Biological and Biomedical Sciences to continue his studies on the pathogenesis of retinal degeneration.
Understanding the pathogenesis and developing therapeutic strategies for retinal diseases.
Pathogenesis of Retinitis Pigmentosa. Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degeneration with a worldwide prevalence of 1 in 4000. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common single cause of RP, accounting for 10-20% of cases. The function of RPGR is unclear, although the N-terminal half of RPGR is structurally similar to the regulator of chrosome condensation (RCC1), a guanine nucleotide exchange factor for the small GTP-binding protein, Ran. We firstly found RPGR localised to centrosome/basal body and interacted multi-functional protein, nucleophosmin. RPGR has been shown to co-immunoprecipitate with a number of different axonemal,centrosomal/basal body and microtubular proteins, and its localisation to basal bodies was shown to be dependent on the retrograde dynein-dynactin motor complex. RPGR is a component of one or more protein complexes, which at the same or different times are concerned either with docking or transport along primary or neurosensory cilia. We are trying to characterise the role of RPGR associated protein complexes in the pathogenesis of RP.
Late-onset retinal macular degeneration. Age-related macular degeneration (AMD) accounts for about 50% of blind registrations in Western countries and is a common, genetically complex disorder. A primary feature of AMD is the presence of extracellular deposits between the retinal pigment epithelium (RPE) and underlying Bruch’s membrane, leading to RPE dysfunction, photoreceptor death and severe visual loss. Very little is known regarding its molecular basis. Late-onset retinal macular degeneration (L-ORMD) is an autosomal dominant condition resembling AMD in which a key pathological feature is a thick extracellular sub-RPE deposit. We previously showed that L-ORMD is caused by a single founder mutation (Ser163Arg) in the C1QTNF5 gene. C1QTNF5 encodes an N-terminal signal peptide, a short collagen repeat and a C-terminal globular complement 1q (gC1q) domain, which is necessary for trimerisation of the collagen domain. It is unclear whether the disease results from loss-of-function, such as reduced C1QTNF5 secretion, or gain-of-function, such as formation of abnormal hetero-trimers containing both normal and mutant subunits. Recently we found that C1QTNF5 interacts with complement factor H (CFH), in which polymorphisms significantly influence the risk of developing AMD. Mutant C1QTNF5 (163Arg) shows a twenty-fold higher affinity for full length CFH than wildtype, the mutant also binds the 402His (high AMD risk) allele of CFH with higher affinity than the 402Tyr allele. This provides a working hypothesis that mutant C1QTNF5 results in an adverse gain-of-function leading to AMD-like disease by dysregulation of the alternative complement pathway. We are investigating the effect of the interaction between CFH and C1QTNF5 on CFH function and how this relates to the pathogenesis of macular degeneration.
The role of Oxidative stress in the pathogenesis of diabetic retinopathy
Diabetes is a disease resulting from the elevated blood glucose concentration due to a loss of insulin-producing pancreatic β cells (type 1 diabetes) or through loss of insulin responsiveness in its target tissues (type 2 diabetes). Diabetic retinopathy (DR) is the leading cause of blindness for working –age individuals, 78-98% diabetes will progress to DR within 15 years of diagnosis. Oxidative stress is believed to play a key role in the development of DR. High glucose levels increase the release of reactive oxygen species (ROS), superoxide levels are increased in the retina of diabetic rat and in retinal cells growing within high glucose media In diabetes, the activities of anti-oxidative enzymes responsible for scavenging free radicals and maintaining redox homeostasis such as superoxide dismutase (SOD), glutathione reductase, glutathione peroxidise, and catalase are diminished in the retina. We will investigate the functional of some key antioxidant enzymes in the pathogenesis of DR. Outcomes of the project will enable us to understand the disease mechanisms of DR and help to develop therapeutic strategies for treating patients with DR.
Zebrafish as a model for retinal diseases. The vertebrate neural retina shows strong evolutionary conservation. The anatomy, histology and function of the zebrafish retina closely resembles human retina, with the same major classes organised in the same laminar pattern. We recently used zebrafish as a model to investigate RPGR function. Zebrafish has two RPGR genes (ZFRPGR1 and ZFRPGR2) resembling human RPGR, both of which are expressed within the nascent and adult eyes as well as more widely during development. ZFRPGR2 appears to be functionally orthologoius to human RPGR and causes developmental defects similar to other ciliary proteins, affecting gastrulation, tail and head development after morpholino-induced knock-down. These defects are consistent with a ciliary function and were rescued by human RPGR but not by RPGR mutants causing retinal dystrophy. Knock-down of ZFRPGR2 also resulted in an intracellular transport defect affecting retrograde but not anterograde transport of organelles. The zebrafish model provides us with a unique opportunity to directly address the consequence of mutations found in human RPGR disease. We aim to set up a solid platform to test for loss- or gain-of-function of RPGR mutations before proceeding to gene therapy. We also plan to use zebrafish model to study the disease mechanisms of other retinal diseases.
Selected recent Publications: