A role of chromatin remodeling complexes in beta cell dysfunction

项目总结/摘要 由炎症和其他类型的应激引起的胰岛细胞功能障碍在型糖尿病的发病机制中至关重要。 2型糖尿病（T2 D）。因此，旨在保护胰岛细胞免受功能障碍的策略可能对 防治糖尿病。这位候选人之前的研究表明，维生素A和维生素E之间的配体依赖性开关 D受体（VDR）相关的布罗莫结构域阅读器BRD 9和BRD 7调节抗炎作用。 反应的细胞。VDR激活和BRD 9抑制的组合促进了VDR-BRD 7缔合， 在多种小鼠T2 D模型中，抑制胰岛细胞中的炎症并改善葡萄糖稳态。BRD9 BRD 7和BRD 7分别属于BAF和PBAF，两个重叠但功能不同的SWI/SNF 染色质重塑复合物因此，染色质重塑复合物可能在细胞凋亡中起重要作用。 T2 D中的细胞功能障碍。该建议的假设是BAF和PBAF复合物之间的平衡， 由BRD 9/BRD 7调节，控制着胰岛细胞表观基因组和代谢稳态。探讨 基因调控机制与胰岛细胞功能障碍有关，这里提出的研究将联合收割机 通过基因组、分子和遗传学方法来确定SWI/SNF复合物在调节细胞凋亡中的作用， 表观基因组和功能在T2 D中的作用，具体目标如下：目标1：确定SWI/SNF复合物在T2 D中的平衡 通过绘制关键BAF和PBAF复合物的基因组分布， 目的2：表征SWI/SNF介导的染色质可及性动力学在形成细胞超 目的3：使用CD 34细胞特异性敲除小鼠模型来确定增强子活性的作用和下游调节。 BRD 9/BAF在体内的靶点。总的来说，这些研究可能揭示了两个之间的微调平衡 竞争性染色质重塑复合物控制T2 D中的细胞功能，并可能导致新的策略 用于开发直接针对胰岛细胞功能障碍的下一代抗糖尿病疗法。 候选人在未来三年的目标是发展一个独立的研究计划， 糖尿病，核受体和表观遗传学领域，并过渡到一个学术教师的位置。他 在转录、表观遗传学和代谢方面接受过广泛的背景培训。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，了解转录调控，以及如何 控制着胰岛细胞的生理机能。Mark Huising博士是一位胰岛生物学家，他将担任共同导师， 接受过细胞生理学和成像方面的培训。候选人将继续与他的共同导师，博士合作。 Diana Hargreaves，获得与染色质重塑相关的生物化学和基因组测定方面的专业知识。 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人员， 学术机构，研究糖尿病和炎症的分子基础。该奖项还将使 他希望发展自己的研究领域，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.