3. Discussion
3.4. Outlook
Despite a novel understanding of the Ubiquitin-proteasome ƉĂƚŚǁĂLJŝŶƉĂŶĐƌĞĂƚŝĐɴ-cell survival and function provided in the current study, many outstanding questions exist, which would be of great interest to further investigate in the near future:
1. The upstream regulators or an upstream signaling pathway that controls the level of FBXO28 protein especially under diabetic conditions.
2. dŚĞ ɴ-cell specific FBXO28 substrates need to be identified. Further studies on the physiologiĐĂů ĨƵŶĐƚŝŽŶƐ ŽĨ ƚŚĞ &yKϮϴ ƐƵďƐƚƌĂƚĞƐ ŝŶ ɴ-cell survival and function are required to understand the molecular mechanisms ŽĨ&yKϮϴĂĐƚŝŽŶŝŶɴ-cell biology.
3. ɴ-cell specific FBXO28 transgene/knockout mice studies would provide further insights into the physiological regulation and function of FBXO28 at the cellular, molecular and organismic level in the control of metabolism.
4. Having established the anti-ĂƉŽƉƚŽƚŝĐ ĞĨĨĞĐƚ ŽĨ h^Wϭ ŝŶŚŝďŝƚŝŽŶ ŝŶ ɴ-cells and isolated human islets in vitro, it is necessary to investigate the impact of USP1 inhibition in ƉĂŶĐƌĞĂƚŝĐɴ-ĐĞůůŝŶƚĞƌŵƐ ŽĨƐƵƌǀŝǀĂůŝŶǀŝǀŽ͘ɴ-cell specific USP1 knockout mice would ƉƌŽǀŝĚĞĨƵƌƚŚĞƌŝŶƐŝŐŚƚƐŝŶƚŽƚŚĞƉŚLJƐŝŽůŽŐŝĐĂůƌŽůĞŽĨh^WϭŝŶɴ-cells in vivo.
5. /ĚĞŶƚŝĨŝĐĂƚŝŽŶŽĨh^Wϭɴ-cell specific substrates, their physiological role in the context of ɴ-cell survival, function, and DDR would reveal therapeutic insightƐ ŝŶ ƌĞƐĐƵŝŶŐ ɴ-cell from DDR induced apoptosis towards diabetes treatment.
6. In depth in vivo experiments, full toxicology and pharmacology and pre-clinical studies with currently available USP1 inhibitors need to be performed in order to develop them as potential therapeutic molecules.
Discussion
91
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