Targeting The HDAC6-Cilium Axis Ameliorates The Pathological Changes Associated With Retinopathy Of Prematurity

Retinopathy of prematurity(ROP)is a major ocular disorder in premature infants and the leading causes of visual loss in childhood worldwide.The sequential oxygen changes,namely exposure of infants to high oxygen(hyperoxia)and then normal oxygen(relative hypoxia),which cause abnormal growth of retinal blood vessels resulting in retinal detachment,are believed as the key factor that contributes to ROP.Laser therapy and cryotherapy,interventions directed against retinal detachment,are the most effective treatments for ROP.Unfortunately,these treatments are associated with significant tissue injury,leading to partial loss of side vision.Meanwhile,there are still very few effective pharmacological interventions for the specific prevention or treatment of premature infants with ROP,thus novel effective small molecular agents are warranted for the clinical interventions.Retina,as the basic structure of the visual system,is located on the inner surface of the posterior eyes.It functions to convert light to electrical impulses and transmits this information to visual processing centers in the brain so that this sensory information can be interpreted as vision.Photoreceptors are the most abundant sensory neurons of the retina and are responsible for converting light signals into electrical signals,a biological process called phototransduction.The photoreceptor is organized into three specialized compartments: an outer segment where the processes underlying vision are initiated,an inner segment that houses the biosynthetic machinery required for protein synthesis,and a synaptic terminal for signal transmission.The outer segment,also called photoreceptor cilium,is characterized by hundreds of light sensitive membranous discs stacked in a precise pattern,which distinct from common primary cilium.Studies over the past few decades indicate that structural deficits and/or dysfunction of the photoreceptor cilium can cause photoreceptor degeneration and visual impairment,leading to retinal diseases.We have previously revealed that histone deacetylase 6(HDAC6)is upregulated during the transition from hyperoxia to relative hypoxia.We also demonstrate that HDAC6 upregulationinduced photoreceptor cilium disassembly is an early event in response to oxygen changes.Thus,we hypothesized that HDAC6-mediated disassembly of the photoreceptor cilium may represent a main cause for ROP and that targeting the HDAC6-cilium axis may prevent the pathogenesis of this disease.In this thesis,to investigate the pathological function of HDAC6-mediated photoreceptor cilium disassembly in the pathogenesis of ROP,we use multiple biological method,such as intravitreal injection techniques,immunohistochemistry,electroretinography(ERG)and transmission electron microscopy,and various mouse models including HDAC6 transgenic mice,HDAC6 knockout mice and oxygen-induced retinopathy(OIR)mouse model.We found that intravitreal injection of an adenovirus encoding HDAC6 resulted in mice exhibiting ROP-related phenotypes,including damage to the retinal photoreceptor layer and abnormalities in the ERG.In addition,HDAC6 transgenic mice were also found to exhibit ROP-related phenotypes,and knockdown of HDAC6 or intravitreal injection of small-molecule compounds that inhibit HDAC6-mediated photoreceptor cilium disassembly protected mice from retinopathy induced by oxygen changes.In summary,we elucidate the mechanism of HDAC6-mediated photoreceptor cilium disassembly in ROP and reveal the value of targeting HDAC6-cilium axis for intervention in ROP.The findings indicate that pharmacological targeting of the HDAC6-cilium axis may represent a promising strategy for the prevention of ROP.