Characterization of transcriptome changes in diet-induced progression to METS/T2D to identify earliest and sex-specific neurodegenerative foci for AD development

饮食诱导的 METS/T2D 进展中转录组变化的表征，以确定 AD 发展的最早和性别特异性神经退行性病灶

• 批准号: 10359377
• 负责人: Gemma Casadesus
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359377
• 关键词: Characterization; transcriptome; changes; diet; induced; Characterization; transcriptome; changes; diet; induced

Project Summary Metabolic resistance (METS) and type II diabetes (T2D) hold one of the strongest associations with AD development, however, we know little in terms of how, at a precise mechanistic level, this prodromal metabolic phenotype actually leads to neurodegenerative changes that ultimately result in AD. We know equally little about how sex contributes in accelerating or slowing this progression and how known sex-specific differences for METS/T2D and AD affect this relationship. Given that the incidences of both diseases are skyrocketing, understanding these aspects is critical to develop optimal early/preventative therapeutic interventions for individuals with METS/T2D, at high risk for AD. However, addressing these questions using single targeted hypothesis-based approaches is difficult given the multifactorial nature of potential interactions (multiple disease factors, time, and sex) and is further confounded by changing/incomplete experimental designs across animal studies. To address these challenges, we seek to study the relationship between METS/T2D progression and AD in a more global genome-wide manner, coupled with powerful statistics and biochemical measurements to gain a clearer picture of the METS/T2D-AD relationship. Specifically, we propose to determine alterations in transcriptome, AD and METS-related mitochondrial, metabolic, and pathology changes, in both sexes, over time. We will use bioinformatics and large-scale statistical analysis tools to identify associations across these variables, in addition to sex hormone levels, and time. We will couple these observations with modifications of mitochondrial and metabolic genes (affected early in both diseases) and novel ones discovered via RNA seq to interrogate these relationships mechanistically in vitro.

项目摘要 代谢性（MetS）和II型糖尿病（T2D）保持与AD最强的关联之一 但是，发展，我们对在精确的机械水平上如何了解这种前驱代谢几乎不了解 表型实际上导致神经退行性变化，最终导致AD。我们对 性别如何加速或减慢这种进步以及已知的性别特异性差异的贡献 Mets/T2D和AD会影响这种关系。鉴于两种疾病的发生率都在飞涨， 了解这些方面对于开发最佳的早期/预防性治疗干预措施至关重要 具有MetS/T2D的个体，AD高风险。但是，使用单一的目标解决这些问题 鉴于潜在相互作用的多因素性质（多重疾病），基于假设的方法很难 因素，时间和性别），并通过动物的改变/不完整的实验设计来进一步混淆 研究。为了应对这些挑战，我们试图研究Mets/T2D进展与 以更全球的全基因组方式进行广告，再加上强大的统计数据和生化测量 了解Mets/T2D-AD关系的清晰图片。具体来说，我们建议确定 随着时间的流逝，两性的转录组，AD和与MetS相关的线粒体，代谢和病理变化。 我们将使用生物信息学和大规模统计分析工具来识别这些关联 变量，除了性激素水平和时间。我们将将这些观察结果与修改 线粒体和代谢基因（在疾病的早期受到影响）和通过RNA SEQ发现的新颖基因 在体外对这些关系进行询问。