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Role of intestinal luminal and epigenetic factors to mediate intestinal metabolic remodeling after gastric bypass surgery - Administrative Supplement

肠腔和表观遗传因素在胃绕道手术后介导肠道代谢重塑中的作用 - 行政补充

基本信息

批准号：
10852453
负责人：
Margaret Stefater-Richards
金额：
$ 8.4万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-09-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY The rising incidence of type 2 diabetes (T2D) highlights a growing need to understand mechanisms behind highly-effective therapies such as Roux-en-Y gastric bypass surgery (RYGB) in order to develop better, more widely-applicable treatments. The long-term goal is to understand the role of luminal factors to mediate the effect of intestinal re-routing upon energy metabolism, including T2D. The overall objective of this project is to test for tissue-level epigenetic changes in the intestine after RYGB, as a potential mechanism for Roux limb (RL) remodeling that we have shown to relate to T2D remission in humans. The central hypothesis is that RL metabolic reprogramming is driven by segment-specific epigenetic modifications which are plastic and require continuous luminal stimulation. The rationale for this project is that a greater understanding of intestinal gene expression regulatory networks after RYGB will shed light on ways to mimic RYGB’s effects with less invasive alternative therapies. The central hypothesis will be tested in two specific aims: (1) to test the role of an unexpected luminal nutrient load to influence RL epigenetic and transcriptomic signatures for key genes associated with metabolically-significant RL remodeling; and (2) to test the dependency of RL epigenetic signatures and metabolic substrate utilization upon in vivo factors using intestinal epithelial organoids (IEOs). In aim 1, gene expression (RNA-seq) and chromatin remodeling (ATAC-seq) will be studied in RL versus bypassed intestinal limb (biliopancreatic limb) or versus sleeve gastrectomy, and these methods will also be employed to test the plasticity of RL remodeling during caloric restriction and refeeding. In aim 2, IEOs will be used to ask whether epigenetic (ATAC-seq) and metabolic reprogramming (RNA-seq; Seahorse XF Analysis) change in the absence of in vivo factors. Dr. Margaret Stefater-Richards, is a pediatric endocrinologist with an MD/PhD and expertise in the integrated physiology of energy balance, especially after bariatric surgery. In order to achieve scientific independence for the candidate, a comprehensive career development plan has been developed to gain additional experience in the areas of (1) epigenetics and gene regulatory networks, (2) bioinformatics, and (3) use of intestinal organoids as a model of intestinal biology. This extension will facilitate completion of hands-on and formal training in epigenetics and the intestinal biology underlying bariatric surgery, under the mentorship of experts in the fields of bariatric surgery (Mary Elizabeth Patti) and intestinal biology (David Breault). The research in this application is innovative, representing a substantial departure from the status quo by using state-of-the-art sequencing and bioinformatics techniques to address how RYGB’s core surgical elements (e.g., biliary exclusion, accelerated nutrient delivery) influence epigenetic regulation of gene expression. Ultimately, this project will shed light on mechanisms linking luminal factors to known intestinal remodeling after RYGB, thus highlighting potential novel drug targets for the development of innovative T2D therapies, and paving the way for the applicant’s first R01 submission.

项目摘要 2型糖尿病（T2 D）发病率的上升凸显了对了解其背后机制的日益增长的需求。高效的治疗方法，如Roux-en-Y胃旁路手术（RYGB），以开发更好，更广泛适用的治疗。长期的目标是了解管腔因子在介导细胞凋亡中的作用。肠道改道对能量代谢的影响，包括T2 D。该项目的总体目标是 RYGB后肠道组织水平表观遗传变化的测试，作为Roux肢体的潜在机制 (RL)我们已经证明与人类T2 D缓解有关的重塑。核心假设是RL 代谢重编程是由片段特异性表观遗传修饰驱动的，这些表观遗传修饰是可塑的，连续的腔刺激。这个项目的基本原理是， RYGB后的表达调控网络将揭示如何模拟RYGB的影响，替代疗法中心假设将在两个特定的目标进行测试：（1）测试的作用，意想不到的管腔营养负荷影响RL表观遗传和转录组特征的关键基因与代谢显著的RL重塑相关;和（2）测试RL表观遗传的依赖性，使用肠上皮类器官（IEO）的体内因子的特征和代谢底物利用。在目标1中，将在RL与对照组中研究基因表达（RNA-seq）和染色质重塑（ATAC-seq）。旁路肠分支（胆胰分支）或相对于袖状胃切除术，这些方法也将用于测试在热量限制和再喂养期间RL重塑的可塑性。在目标2中，国际教育组织将用于询问表观遗传（ATAC-seq）和代谢重编程（RNA-seq;海马XF分析）在缺乏体内因素的情况下发生变化。Margaret Stefater-Richards博士是一位儿科内分泌学家， MD/PhD和能量平衡综合生理学方面的专业知识，尤其是减肥手术后。在为了实现候选人的科学独立性，全面的职业发展计划已开发，以获得更多的经验，在该领域的（1）表观遗传学和基因调控网络，（2）生物信息学，以及（3）使用肠类器官作为肠生物学的模型。这一扩展将有助于完成表观遗传学和减肥基础肠道生物学的实践和正式培训外科，在减肥手术（玛丽伊丽莎白帕蒂）和肠道领域的专家指导下，生物学（大卫布洛特）。这项应用的研究是创新的，代表了一个实质性的偏离。通过使用最先进的测序和生物信息学技术， RYGB的核心手术要素（例如，胆汁排除，加速营养输送）影响表观遗传基因表达的调控。最终，该项目将揭示腔因子与 RYGB后已知的肠重塑，从而突出了潜在的新药物靶点的发展，创新的T2 D疗法，并为申请人的第一个R 01申请铺平道路。