Targeting histone deacetylase 3 for chronic kidney disease

项目总结 慢性肾脏疾病(CKD)是一个公共卫生问题，影响着2600多万美国人。 退伍军人中CKD的患病率比普通美国人高34%。一把钥匙 慢性肾脏病的病理特征是肾脏炎症导致慢性肾脏疾病的发生和发展。 到终末期肾病。目前这种进行性疾病的治疗选择是有限的，而且通常 效果不佳。因此，更好地理解肾脏炎症的分子机制是 这对于制定治疗慢性肾脏病的有效策略至关重要。 我们研究了引发和控制肾炎的因素，发现了一个关键的 组蛋白脱乙酰酶3(HDAC3)在慢性肾脏病肾组织炎症调控中的作用 我们的初步研究表明，巨噬细胞的激活和产生 促炎症细胞因子依赖于肾脏中HDAC3的诱导。基因缺失或 HDAC3的药理抑制可阻止巨噬细胞激活和促炎分子的产生。 此外，HDAC3的促炎作用似乎是通过调节核因子kappa来实现的。 B(核因子-kB)信号通路。在本应用程序中，我们计划检查和表征HDAC3在 巨噬细胞的激活和促炎分子的产生进一步了解细胞和分子 肾脏炎症的机制。我们的中心假设是HDAC3去乙酰化组蛋白，导致 染色质重塑，允许核因子-kB进入其DNA反应元件诱导促炎 分子表达。为了验证我们的假设，我们将追求以下具体目标：具体目标1是 确定HDAC3在巨噬细胞激活和促炎分子产生中的作用；特异性 目的2探讨HDAC3促进巨噬细胞活化的分子机制。 促炎分子的产生；而具体目标3是评估选择性的 慢性肾脏病的HDAC3抑制剂。 综上所述，我们计划利用分子、细胞、药理学和遗传学方法来研究 HDAC3在巨噬细胞活化和肾损伤发生发展中的作用我们的研究结果将提供 对肾脏炎症的细胞和分子机制有新的认识，并可能导致 开发治疗慢性肾脏病的新治疗策略。

PROJECT SUMMARY Chronic kidney disease (CKD) is a public health problem that affects more than 26 million Americans. The prevalence of CKD in the veteran population is 34% higher than in the general US population. A key pathologic feature of CKD is renal inflammation resulting in initiation and progression of chronic kidney disease to end-stage kidney disease. The current therapeutic options for this progressive condition are limited and often ineffective. Therefore, a better understanding of the molecular mechanisms underlying renal inflammation is essential for developing effective strategies for the treatment of CKD. We have studied the factors initiating and controlling renal inflammation and have discovered a critical role of histone deacetylase 3 (HDAC3) in the regulation of renal inflammation during the development of CKD. Our preliminary studies have demonstrated that the activation of macrophages and the production of proinflammatory cytokines are dependent upon induction of HDAC3 in the kidney. Genetic deletion or pharmacological inhibition of HDAC3 prevents macrophage activation and proinflammatory molecule production. Furthermore, the proinflammatory effect of HDAC3 appears to be mediated by regulating nuclear factor kappa B (NF-kB) signaling pathway. In this application, we plan to examine and characterize the role of HDAC3 in macrophage activation and proinflammatory molecule production to further understand the cellular and molecular mechanisms of renal inflammation. Our central hypothesis is that HDAC3 deacetylates histones resulting in chromatin remodeling, which allows NF-kB to access its DNA response elements to induce proinflammatory molecule expression. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of HDAC3 in the macrophage activation and proinflammatory molecule production; Specific Aim 2 is to explore the molecular mechanisms by which HDAC3 promotes macrophage activation and proinflammatory molecule production; and Specific Aim 3 is to evaluate the therapeutic potential of a selective HDAC3 inhibitor for CKD. In summary, we plan to utilize molecular, cellular, pharmacological, and genetic approaches to study the role of HDAC3 in macrophage activation and development of renal injury. Results from our studies will provide a new understanding of the cellular and molecular mechanisms of renal inflammation and could lead to the development of novel therapeutic strategies for the treatment of CKD.