Research Projects
Retinal Neurodegeneration and Retinal Ischemia in Diabetic Retinopathy – Association with Autophagy Dysfunction

Diabetic retinopathy (DR) is a devastating disease and has been regarded as a microvascular disease as most visible clinical features of DR are microvascular irregularities. This concept has now evolved to one in which neurodegeneration occurs as an early event in DR and plays important roles in the pathogenesis of DR. Autophagy has been identified as a hallmark of neurodegeneration. Autophagy is an evolutionary conserved mechanism that allows the cell to degrade damaged proteins and intracellular organelles, thereby maintaining cell homeostasis against cellular stress. However, autophagy can turn to be detrimental when it is excessively up-regulated, leading to cell death in ischemic events. Retinal ischemia also causes neuronal injury and leads to irreversible neuronal damage and loss and thus visual impairment. Since treatment options to salvage damaged retinal neurons are inadequate with sub-optimal outcomes, we aim to establish the crucial role of autophagy in retinal neurodegeneration and retinal ischemia-associated neuronal damage in the diabetic retina for future implementation of a more timely therapeutic approach in early DR. We have investigated the expression of autophagic markers in Ins2Akita/+ mice, a type I diabetes model. These mice carry a mutation in the insulin 2 gene, leading to insulin mis-folding and ultimately β-cell death. They display hyperglycaemia starting at 4-5 weeks of age. Our preliminary results showed an up-regulation of autophagic markers in 6-month-old Ins2Akita/+ mice retinae under prolonged hyperglycaemic condition. Interestingly, retinal ischemia/reperfusion injury is exacerbated with a further increase in autophagic marker level in these retinae. In retinal precursor cells exposed to high glucose level, hypoxia resulted in significant autophagic up-regulation, in parallel with our in vivo results. Both findings point to the importance of autophagy in diabetic retinal neurodegeneration and retinal ischemia in early DR. In light of this, we hypothesise that autophagy dysregulation is detrimental to neuronal survival and is associated with increased neurodegeneration in diabetic retinal degeneration and retinal ischemia. In this proposal, we will use the Ins2Akita/+ mice as an animal model of early DR to 1) identify autophagic events and evaluate the effects of its inhibition by rapamycin in retinal neurodegeneration in early DR, and 2) to investigate and compare the autophagic response of retinal neurons to ischemia with or without chronic hyperglycaemia. Our work will not only increase our understanding on DR but also provide evidence that neuroprotection targeting the autophagy pathway can be a potential DR therapeutic strategy for retinal neurodegeneration, an early occurrence in DR.

Professor ACY Lo, Department of Ophthalmology

Professor Amy Lo obtained her PhD from the Department of Neuroscience in the Johns Hopkins University School of Medicine. One of the PI's research themes is neuroprotection in the eye using disease models such as transgenic and knockout mice, rats and rabbits as well as in vitro models using primary cells and cell lines. She is well trained in morphological, functional, cellular, and molecular analyses of the eye and brain. Professor Amy Lo has been using genetic and pharmacological manipulations to identify potential therapeutic targets for various ocular diseases. She has track record on age-related macular degeneration, diabetic retinopathy, cerebral and retinal ischemia/reperfusion injury, oxygen-induced retinopathy, retinal degeneration, and intraocular drug delivery.

Biography
HKU Scholars Hub
ORCID
amylo@hku.hk

For more information or to express interest for this project, please email the supervisor or the specified contact point in the project description.  Interested candidates are advised to enclose with your email:

1. your CV,
2. a brief description of your research interest and experience, and
3. two reference letters (not required for HKUMed UG students seeking MRes[Med]/URIS projects).

Information on the research programme, funding support and admission documentations could be referenced online at the Research Postgraduate Admissions website. General admission enquiries should be directed to rpgmed@hku.hk.

HKUMed MBBS students interested in the Master of Research in Medicine (MRes[Med]) programme may visit the programme website for more information.  

HKUMed UG students interested in the Undergraduate Research Internship Scheme (URIS) may visit the scheme’s website for more information.