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OBJECTIVES/GOALS: Retinal inflammation caused by the activation of resident macrophages (microglia) during diabetes exacerbates glial cell dysfunction, resulting in neuronal loss. The goal is to use rAAV gene therapy to deliver neuronal-derived fractalkine (FKN), minimizing inflammation and vascular damage in the diabetic retina. METHODS/STUDY POPULATION: The human microglial receptor (CX3CR1) binds to FKN, a protein that is expressed on neuronal membranes (mFKN), and undergoes constitutive cleavage to release a soluble domain (sFKN). Deficiencies in CX3CR1 or FKN showed increased microglial activation and elevated retinal pathology. To understand the mechanism by which mFKN and sFKN regulate microglia function, recombinant adeno-associated viruses (rAAVs) expressing mFKN or sFKN were delivered to intact retinas during diabetes. Markers of neuronal loss, vascular damage, and inflammation were analyzed. We hypothesize that the administration of rAAV-sFKN but not rAAV-mFKN will prevent vascular and neuronal damage, and improve visual function. RESULTS/ANTICIPATED RESULTS: rAAV-sFKN minimized microglial activation, blood vessel rupture, fibrinogen deposition, and prevented neuronal loss, compared to mice treated with rAAV-mFKN in a mouse model of diabetic retinopathy (DR). rAAV-sFKN treated mice showed improved visual acuity using a two-choice discrimination task through learning-based behavior. rAAV-sFKN treatment correlated with the success rate of the mice finding the reward based on their ability to distinguish visual cues. Future studies will test the effects of rAAV-sFKN and rAAV-mFKN on microglia inflammatory cytokine release, optic nerve damage and synaptic neurotransmission, peripheral immune responses, and transcriptomic changes in microglia during diabetes. DISCUSSION/SIGNIFICANCE: Current therapies for DR are ineffective in restoring vision. rAAVs-sFKN delivery appears to act as a neuroprotective approach in the diabetic retina. sFKN serves as an alternative pathway to implement translational and therapeutic approaches, minimizing pathology and improving visual function.
Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFα, lymphotoxin α (LTA), and lymphotoxin β (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFα contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine.
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