The Role of Sirt6 in Acrolein-Induced Ocular Injury - The Role of Sirt6 in Acrolein-Induced Ocular Injury SUMMARY Acrolein is a small, thiol-reactive electrophile and volatile aldehyde that is highly toxic and readily penetrates biological tissues. Historically, it was deployed as a chemical weapon during World War I. In modern times, acrolein remains a chemical of concern due to its widespread use in industrial processes. Large amount of acrolein is produced and transported across the United States annually, heightening the risk of accidental exposure or terrorist-related hijacking. Exposure to acrolein in the eyes causes irritation, pain, eyelid swelling and corneal damages including burns, erosions, clouding and neovascularization. Currently, there is no effective treatment to stop or reverse acrolein-induced ocular injury. Thus, it is a critical need to better understand the mechanisms underlying acrolein-induced ocular injury and to develop innovative, targeted therapies. Sirtuin 6 (Sirt6) is NAD+-dependent histone H3 lysine 9 (H3K9) and H3K56 deacetylase that regulates diverse pathways involving in inflammation, neovascularization, fibrosis, DNA repair, genomic instability, cell death and senescence. These features offer Sirt6 as an excellent candidate for regulating corneal injury after acrolein exposure. Sirt6 plays critical roles in many diseases such as cancer, bone loss, cardiovascular disease and nephropathy. It is abundantly expressed in the cornea. Nevertheless, its role in the corneal diseases including ocular injury after corneal chemical burn has never been assessed. This work will characterize the pathological changes in the cornea and retina induced by corneal acrolein burn using our newly developed mouse model and test the hypothesis that Sirt6 plays a crucial role in mitigating corneal and retinal injury following corneal acrolein burn. We will employ integrated approaches including comprehensive histological analysis and novel imaging-based approaches to assess the degree of acrolein-induced corneal and retinal damage and monitor the effectiveness of boosting Sirt6 expression in mitigating corneal and retinal injury after corneal acrolein burn. Moreover, we will use single-cell RNA sequencing (scRNAseq) to explore the underlying molecular and cellular mechanisms. Completion of the proposed studies will provide critical new insights into the mechanisms of acrolein-induced ocular injury. Given that we and others have developed Sirt6 activators with distinct specificities and desirable drug profiles, the outcomes of this project could pave the way for innovative therapeutic strategies to mitigate both corneal and retinal damage following acrolein burn by using emerging Sirt6 activators.
