Disease Modeling Core

下一代测序(NGS)技术的出现使识别完整的 单个个体的遗传变异谱。这使得识别罕见的变种成为可能 导致人类遗传性疾病。然而，这很快就产生了对证明或 证明候选基因是有因果关系的。开始了解特定基因的一种机制 在帕金森病病理生理学背景下的变化是为了确定表达变化的影响 候选基因中有关键的细胞通路、分子功能和调控网络，所以 称为通路分析。通过检查特定候选人的击倒或击倒的效果 基因在转录组上，我们就可以开始识别导致疾病的关键途径 表型。为此，已经建立了一个综合的、多组织的疾病建模核心，以带来 在酵母、斑马鱼和诱导多能干细胞(IPSCs)建模方面的专业知识。每种型号 核心中的有机体代表了不同程度的复杂性，可以用来更好地理解 帕金森病病理的不同方面。这一核心将有助于快速识别大多数 检验特定基因功能丧失的影响的适当模型(源自项目1 和3)和非编码RNA(项目2)在转录组上(在核心C中分析)。击倒或 将在适当的生物体中开发特定候选基因的敲除模型，以提供 用于转录组分析的生物材料(总RNA)。除了提供来自 敲除/敲除细胞和组织(以及控制细胞和组织)，这个核心将产生重要的 用于未来功能研究的试剂(吗啉、shRNAs、酵母敲打菌株和ipscs) UM Udall中心成员以及其他Udall中心和PD调查人员的PD病理。

The advent of next generation sequencing (NGS) technologies has made it possible to identify the full spectrum of genetic variations in single individuals. This has made it possible to identify rare variants that contribute to human genetic diseases. However, this has quickly created a need for mechanisms to prove or demonstrate that the candidate genes are causal. One mechanism to begin to understand specific genetic variations in the context of the pathophysiology of PD is to identify the impact that changes in the expression of the candidate genes have on key cellular pathways, molecular functions and regulatory networks, so called pathway analysis. By examining the effect that the knockout or knockdown of specific candidate genes have on the transcriptome, we can begin to identify the key pathways responsible for the disease phenotype. To that end, an integrated, multi-organism disease modeling core has been established to bring together expertise in yeast, zebrafish and induced pluripotent stem cells (IPSCs) modeling. Each model organism in the core represents a different level of complexity and can be used to better understand different aspects of the pathology of PD. This core will facilitate the rapid identification of the most appropriate models for examining the impact that loss of function of specific genes (derived from Project 1 and 3) and non-coding RNAs (Project 2) have on the transcriptome (analyzed in Core C). Knockdown or knockout models of the specific candidate genes will be developed in the appropriate organisms to provide the biological material (total RNA) for transcriptome analysis. In addition to providing total RNA from the knockout/knockdown cells and tissues (and control cells and tissues), this core will generate important reagents (morpholinos, shRNAs, yeast knock strains and iPSCs) for future functional studies into the pathology of PD for members of the UM Udall Center, as well as, other Udall Centers and PD investigators.