Targeting histone deacetylase 3 for chronic kidney disease

项目摘要 慢性肾脏病（CKD）是一个公共卫生问题，影响超过2600万美国人。 CKD在退伍军人人群中的患病率比美国普通人群高34%。一个关键 CKD的病理特征是肾脏炎症，导致慢性肾脏疾病的开始和进展 终末期肾病目前对这种进展性疾病的治疗选择是有限的，并且通常 无效。因此，更好地了解肾脏炎症的分子机制是必要的。 对于开发治疗CKD的有效策略至关重要。 我们研究了引发和控制肾脏炎症的因素，并发现了一个关键的 组蛋白去乙酰化酶3（HDAC 3）在CKD发展过程中调节肾脏炎症的作用。 我们的初步研究表明，巨噬细胞的激活和 促炎细胞因子依赖于肾脏中HDAC 3的诱导。基因缺失或 HDAC 3的药理学抑制防止巨噬细胞活化和促炎分子产生。 此外，HDAC 3的促炎作用似乎是通过调节核因子κ B介导的。 B（NF-kB）信号通路。在本申请中，我们计划检查和表征HDAC 3在以下方面的作用： 巨噬细胞活化和促炎分子的产生，以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HDAC 3使组蛋白去乙酰化， 染色质重塑，这使得NF-kB能够进入其DNA反应元件以诱导促炎性反应， 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HDAC 3在巨噬细胞活化和促炎分子产生中的作用; 目的二是探讨HDAC 3促进巨噬细胞活化的分子机制， 具体目标3是评估选择性促炎分子产生的治疗潜力， HDAC 3抑制剂治疗CKD。 总之，我们计划利用分子，细胞，药理学和遗传学方法来研究 HDAC 3在巨噬细胞活化和肾损伤发展中的作用。我们的研究结果将提供 对肾脏炎症的细胞和分子机制有了新的认识， 开发治疗CKD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.