| Author: | Lam, Hang I Christie |
| Title: | Identification of neuroprotective targets for diabetic retinal neuropathy |
| Advisors: | Tse, Dennis (SO) Chan, Henry (SO) |
| Degree: | Ph.D. |
| Year: | 2022 |
| Subject: | Diabetic retinopathy Photoreceptors -- Physiology Hong Kong Polytechnic University -- Dissertations |
| Department: | School of Optometry |
| Pages: | xix, 440 pages : color illustrations |
| Language: | English |
| Abstract: | Diabetic retinopathy (DR) is one of the most significant complications of diabetes. In terms of public health and clinical aspect, it is one of the most common complications among Type 1 and Type 2 diabetes, in which one-third of diabetic patients suffer from this problem. It is also one of the leading causes of blindness among working aged adults. In parallel to the aging population and the growing prevalence of diabetes, the absolute burden of DR is immense. Although DR is more commonly recognized as a microvascular abnormality, diabetes-induced neurodegeneration is suggested to be the earliest manifestation of DR. Diabetic stress has been documented to affect the survival and deteriorate the functions of several retinal neurons. Recent literature has pointed out that photoreceptor cells, one of the major retinal cell types, could secret inflammatory molecules and produce ROS, contributing to the vasculopathy in DR. Yet, the effect of diabetic stress on the physiology of photoreceptor cells remains elusive. The aim of this Ph.D. study is to investigate the effect of simulated diabetic stress, i.e., presence of elevated glucose and linoleic acid-induced lipotoxicity, on the physiology of photoreceptor cells and to provide insight to develop a new target regimen to tackle this sight-threatening eye disease and preserve vision. This thesis consists of three inter-related studies. In Study 1, we adopted an in-vitro model and demonstrated that high glucose and linoleic acid-induced lipotoxicity decreased cell viability and increased apoptosis in 661w photoreceptor-like cell lines. Concomitantly, simulated diabetic stress deleteriously affected the mitochondria of 661w cells by disrupting the homeostasis of mitochondrial membrane potential (ΔѰM), inducing morphological changes and fragmentation, and impairing mitochondrial functions. The central role of mitochondria in the pathogenesis of DR is further supported by Study 2, in which the proteomic profile changes of the 661w cells incubated in the various simulated diabetic stress conditions were investigated using the SWATH-MS. This study demonstrated that several proteins that are related to mitochondria-induced apoptosis signaling pathway and control of mitochondrial dynamic showed differential expression after incubation under simulated diabetic conditions. The involvement of mitochondrial-mediated cell death was further validated by quantifying the translocation of cytochrome c from mitochondria to cytosol. Based on the above results, the prophylactic effect of Coenzyme-Q10 (CoQ10), an antioxidant with mitochondrial stabilizing abilities on protecting the retina against diabetic induced neurodegeneration, was studied in Type 2 diabetic mouse model (db/db mice). The results showed that db/db mice receiving CoQ10 treatment exhibited a delayed deterioration in b-wave amplitude and a stronger OPs wavelets amplitude in scotopic ERG compared to the PBS treated control. Consistent with these findings, retinal immunohistochemistry assay indicated that db/db mice receiving CoQ10 treatment had a significantly thicker INL layer and a higher cone photoreceptor cell density. The rod bipolar cells of db/db mice receiving CoQ10 treatment also possess significantly more synaptic boutons in the OPL, indicating a preserved synaptic connectivity of the second-order neurons. In addition, CoQ10 treatment was demonstrated to alleviate the level of MMP9 activation and support a stronger mitochondrial function in the retina of db/db mice when compared to the PBS treated control. |
| Rights: | All rights reserved |
| Access: | open access |
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