A role of chromatin remodeling complexes in beta cell dysfunction

项目摘要/摘要 由炎症和其他类型的应激引起的细胞功能障碍在该型糖尿病的发病机制中起关键作用。 2糖尿病(T2D)。因此，旨在保护细胞免受功能障碍影响的策略可能对 抗击糖尿病。该候选人之前的研究发现，维生素之间的一种配体依赖的转换 D受体(VDR)相关的溴区阅读器BRD9和BRD7调节抗炎作用 在细胞中的反应。VDR激活和BRD9抑制的组合促进了VDR-BRD7的结合， 抑制细胞的炎症，并改善多种小鼠T2D模型的葡萄糖稳态。BRD9 和BRD7分别属于BAF和PBAF，这是两个重叠但功能不同的SWI/SNF 染色质重塑复合体。因此，染色质重塑复合体可能在中发挥重要作用。 T2D中的细胞功能障碍。这一建议的假设是BAF和PBAF复合体之间的平衡， 受BRD9/BRD7调控，控制细胞表观基因组和代谢动态平衡。为了调查 与细胞功能障碍相关的基因调控机制，这里提出的研究将结合 基因组、分子和遗传学方法确定SWI/snf复合体在调节细胞中的作用 T2D中的表观基因组和功能，具体目标如下：目标1：确定中SWI/Snf复合体的平衡 通过绘制关键的BAF和PBAF复合体的基因组分布图，了解暴露于炎症信号下的细胞 目的2：表征SWI/snf介导的染色质可及性动力学在细胞超分化过程中的作用 增强活性；目标3：使用细胞特异性基因敲除小鼠模型来确定其作用和下游 BRD9/BAF的体内靶点。总而言之，这些研究可能揭示出两者之间的微调平衡 竞争性染色质重塑复合体控制T2D中细胞的功能，并可能导致新的策略 用于开发直接针对细胞功能障碍的新一代抗糖尿病疗法。 候选人未来三年的目标是开发一个独立的研究计划， 在糖尿病、核受体和表观遗传学领域，并过渡到学术教员职位。他 在转录、表观遗传学和新陈代谢方面有广泛的背景培训。在罗纳德博士的实验室里 埃文斯在索尔克研究所，他继续获得经验，以理解转录调控及其如何 控制细胞生理学。小岛生物学家马克·惠辛博士将担任共同导师，并提供更多 细胞生理学和成像方面的培训。这位候选人将继续与他的合作导师Dr。 戴安娜·哈格里夫斯，获得与染色质重塑相关的生化和基因组分析方面的专业知识。 候选人的长期职业目标是成为一名领先的独立生物医学研究员 学术机构，研究糖尿病和炎症的分子基础。该奖项还将允许 他开发了自己的研究利基市场，并将自己与目前的导师区分开来。

Project Summary/Abstract  cell dysfunction, induced by inflammation and other types of stress, is critical in pathogenesis of type 2 diabetes (T2D). Accordingly, strategies designed to protect  cells from dysfunction could be attractive for combating diabetes. The candidate’s previous study identified that a ligand-dependent switch between vitamin D receptor (VDR)-associated bromodomain readers BRD9 and BRD7 regulates the anti-inflammatory response in  cells. A combination of VDR activation and BRD9 inhibition promoted VDR-BRD7 association, suppressed inflammation in  cells, and improved glucose homeostasis in multiple mouse T2D models. BRD9 and BRD7 belong to BAF and PBAF, respectively, two overlapping but functionally distinctive SWI/SNF chromatin remodeling complexes. Therefore, chromatin remodeling complexes may play essential roles in  cell dysfunction in T2D. The hypothesis of this proposal is that the balance between BAF and PBAF complex, modulated by BRD9/BRD7, controls the  cell epigenome and metabolic homeostasis. To investigate the gene-regulatory mechanisms associated with  cell dysfunction, the studies proposed here will combine genomic, molecular and genetic approaches to pinpoint the role of SWI/SNF complexes in regulating the  cell epigenome and function in T2D, in following specific aims: Aim 1: determine SWI/SNF complex balance in  cells exposed to inflammatory cues by charting the genome distribution of key BAF and PBAF complex components; Aim 2: characterize SWI/SNF-mediated chromatin accessibility dynamics in shaping  cell super enhancer activity; Aim 3: use  cell specific knock-out mouse models to determine the roles and downstream targets of BRD9/BAF in vivo. Collectively, these studies may reveal how a fine-tuned balance between two competing chromatin remodeling complexes controls  cell function in T2D, and may lead to novel strategies for the development of next generation anti-diabetic therapies directly targeting  cell dysfunction. The candidate’s goal for the next three years is to develop an independent research program in the area of diabetes, nuclear receptors, and epigenetics, and to transition into an academic faculty position. He has extensive background training in transcription, epigenetics and metabolism. In the laboratory of Dr. Ronald Evans at the Salk Institute he continues to gain experience to understand transcriptional regulation and how it controls  cell physiology. Dr. Mark Huising, an islet biologist, will serve as co-mentor and provide additional training in  cell physiology and imaging. The candidate will continue to collaborate with his co-mentor, Dr. Diana Hargreaves, to acquire expertise in biochemical and genomic assays related to chromatin remodeling. The candidate’s long-term career goal is to become a leading independent biomedical researcher at an academic institution, investigating the molecular basis of diabetes and inflammation. This award will also allow him to develop his own research niche and distinguish himself from his current mentor.