Leveraging PSEN2 biology to understand 3’UTR regulation in Alzheimer’s disease

利用 PSEN2 生物学了解阿尔茨海默病的 3-UTR 调控

• 批准号: 10849939
• 负责人: Julianna Nicole Brutman
• 金额: $ 8.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10849939
• 关键词: Leveraging; PSEN2; biology; understand; UTR

PROJECT SUMMARY Anorexia nervosa is the deadliest psychological disorder with an estimated 10% lifetime disease mortality rate, while over 1/3 of all cancer patients will die from disease-based anorexia, not the cancer itself. On the opposite end of the spectrum, over 2/3 of US adults are overweight or obese, and this number, as well as the rates of associated comorbidities such as heart disease, diabetes, and cancer, is only expected to increase in the coming years. Despite the opposite directionality of these eating disorders, dysfunctional eating in obesity and anorexia is mediated by common appetite circuitry in the central nervous system (CNS). Numerous studies have documented a coordinated and complex pattern of changes in multiple gene products in these appetite centers following periods of excessive or inadequate eating. These observations strongly suggest that the behavioral decision to eat excessively or inadequately is likely driven by a multitargeted, maladaptive genetic reprogramming process in CNS appetite centers. Thus, a core question is what global process could coordinate such changes in multiple gene products? My published studies have demonstrated that appetite changes align with changes in alternative polyadenylation (APA) in the hypothalamus. APA is a rapid, activity-dependent RNA processing mechanism that regulates mRNA transcript stability, maturation, and localization. I identified a significant APA pattern change on tissue inhibitor of metalloproteinases 2 (Timp2), a gene previously implicated in the development of an obese phenotype. Thus, I am exploring the hypothesis that Timp2 APA in the arcuate nucleus (ARC) of the hypothalamus meters the development of obesity. My proposed experiments in the F99 phase will show that 1) Timp2 mRNA is necessary for appetite control in the ARC, and that 2) APA regulation of ARC Timp2 is necessary to counteract hyperphagia and obesity. These studies will be the first to functionally link APA regulation to feeding behavior and will serve as the basis of further genome to behavioral phenome studies in my independent career. My Sponsor, Dr. Gary Wayman, and Co-Sponsors, Drs. Suzanne Appleyard and Emily Qualls-Creekmore, are established neuroscientists at Washington State University with expertise in molecular neuroscience (Wayman) and ingestive behavior (Appleyard and Qualls-Creekmore). My proposed Research and Training plan will strengthen my theoretical and technical understanding of neurogenetics. In the pre-doctoral F99 phase, I will learn shRNA and CRISPR/SaCas9 vector design and validation strategies, cell culture techniques, stereotaxic surgeries, and advanced metabolic analyses. In the postdoctoral K00 phase, I will build upon these skills and learn to use genetic mouse models, multi-omics, advanced bioinformatics, and AI computational models to map genome to phenome regulation. Overall, the proposed training will optimally position me to start an independent research career at a leading neuroscience research institute and advance our understanding of RNA regulation as a functional link between the genome and the behavioral phenome.

项目摘要 神经性厌食症是最致命的心理疾病，估计有10%的终生疾病死亡率 超过三分之一的癌症患者将死于基于疾病的厌食症，而不是癌症本身。上 相反，超过2/3的美国成年人超重或肥胖，这个数字，以及 相关的合并症，如心脏病，糖尿病和癌症的发病率，预计只会增加， 未来几年。尽管这些饮食失调症的方向相反， 厌食症由中枢神经系统（CNS）中的普通食欲回路介导。大量研究 已经记录了这些食欲中多种基因产物的协调和复杂的变化模式， 中心后，过度或不充分的饮食时期。这些观察结果有力地表明， 过度进食或进食不足的行为决定可能是由一种多靶向的、适应不良的遗传基因驱动的。 中枢神经系统食欲中心的重编程过程。因此，一个核心问题是什么样的全球进程可以协调 在多个基因产物中的这种变化？我发表的研究表明，食欲的变化 下丘脑中的交替多聚腺苷酸化（阿帕）的变化。阿帕是一种快速、活性依赖的RNA， 调节mRNA转录稳定性、成熟和定位的加工机制。我发现了一个 金属蛋白酶组织抑制剂2（Timp 2）的显著阿帕模式变化， 肥胖表型的形成因此，我正在探索的假设是，在弓形的Timp 2阿帕 下丘脑的神经核（ARC）测量肥胖的发展。我在F99上提出的实验 阶段将表明1）Timp 2 mRNA是ARC中食欲控制所必需的，以及2）阿帕调节 ARC Timp 2是对抗食欲过盛和肥胖所必需的。这些研究将是第一个从功能上 将阿帕调节与摄食行为联系起来，并将作为进一步从基因组到行为表型组的基础 在我的独立职业生涯中进行研究。我的赞助商，加里韦曼博士，和共同赞助商，苏珊娜Appleyard博士 和艾米丽Qualls-Creekmore，是华盛顿州立大学的神经科学家， 分子神经科学（Wayman）和摄食行为（Appleyard和Qualls-Creekmore）。我建议的 研究和培训计划将加强我对神经遗传学的理论和技术理解。在 博士前F99阶段，我将学习shRNA和CRISPR/SaCas 9载体的设计和验证策略，细胞 培养技术、立体定位手术和先进的代谢分析。在博士后K 00阶段，我 将建立在这些技能和学习使用遗传小鼠模型，多组学，先进的生物信息学， AI计算模型将基因组映射到表型调控。总的来说，拟议的培训将最佳地 让我在一家领先的神经科学研究机构开始独立的研究生涯， 我们对RNA调节作为基因组和行为表型之间的功能联系的理解。