CDYL介导的组蛋白巴豆酰化在常染色体显性多囊肾病中的作用及其机制研究

常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾病，发病机制不清，缺乏安全有效的治疗手段。最新的研究提示，表观遗传调控在ADPKD的发生发展中发挥重要作用，但具体的机制仍有待阐释。我们的前期结果表明，在ADPKD小鼠模型中，组蛋白巴豆酰化修饰水平显著增加。巴豆酰辅酶A是巴豆酰化修饰的供体分子，表观调控蛋白CDYL可通过将巴豆酰辅酶A转化为β羟基丁酰辅酶A，从而降低巴豆酰化水平。我们发现，囊泡上皮细胞中CDYL表达显著降低。在ADPKD小鼠模型中过表达CDYL可抑制囊肿生长，改善肾脏功能。拟开展的工作将进一步探讨CDYL介导的组蛋白巴豆酰化影响囊肿生长的分子机制，鉴定其调控的下游靶分子并验证靶分子在疾病发生发展中的作用。此研究将有助于我们理解CDYL介导的组蛋白巴豆酰化的病理生理功能，理解表观遗传调控在ADPKD发病中的作用及机制，为发现新的药物作用靶点提供理论基础。

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disease. The molecular mechanisms underlying ADPKD progression remain poorly understood, and safer and more effective treatments are needed. Accumulating evidence suggests that epigenetic regulation plays a key role in ADPKD. Our preliminary data showed that histone crotonylation increased markedly in mouse and human ADPKD kidneys. The chromodomain Y-like protein (CDYL) acts as a crotonyl-CoA hydratase and inhibits histone crotonylation by reducing crotonyl-CoA. We found that CDYL expression was substantially decreased in cyst-lining epithelial cells. Overexpression of CDYL attenuates cyst development in ADPKD mice. The future work will focus on: (1) investigating the molecular mechanism underlying CDYL-regulated histone crotonylation in promoting cystogenesis; (2) identifying downstream target genes of CDYL; (3) verifying the role of these target genes in ADPKD progression. This study will not only help us understand the pathophysiology function of CDYL-mediated histone crotonylation and the role of epigenetic regulation in the pathogenesis of ADPKD, but also provide us a basis for designing new treatment strategies.