Studying the mechanisms of novel therapeutic compounds for Parkinson's Disease in complimentary in vitro and in vivo models

在互补的体外和体内模型中研究帕金森病的新型治疗化合物的机制

• 批准号: 2114890
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2114890
• 关键词: Studying; mechanisms; novel; therapeutic; compounds

This project is a collaboration between two supervisors from the Neuroscience department at University of Sheffield, an industrial partner and two collaborators brining in vivo expertise from Florida and Oregon, USA. The industrial partner has already agreed to the MRC iCase studentship terms and sent a letter of collaboration to confirm. The project builds upon existing work in the laboratories of the supervisors on Parkinson's disease. We were the first group worldwide to report mitochondrial dysfunction in peripheral patient cells from patients with genetic forms of Parkinson's disease. Subsequently, we undertook the first ever drug screen using patient cells in Parkinson's disease which focused on compounds which can provide mitochondrial improvement. Subsequent to this the primary supervisor has established more advanced compound screens and complimentary patient derived neuron models for testing prospective therapeutics. In a collaboration with the industrial partner we have screened ~200 novel compounds in the patient derived fibroblasts and neurons. Based upon the data from these assays compounds have been selected for additional testing in animal models of Parkinson's disease. For this we initiated a collaboration with two leading research laboratories, one with a genetic mouse model of Parkinson's; the other with a chronic toxin induced model of Parkinson's. This PhD student project will aim to fully investigate the mechanism with which the selected compounds are producing a recovery effect in these complimentary models of Parkinson's. The project will include, not only time at the industrial partner but also at the collaborator laboratories in Florida and Oregon. This will enable the student to fully investigate the mechanistic pathways activated by these compounds in patient derived neurons in Sheffield (both genetic and sporadic forms), in a genetic mouse model and a toxin induced animal model. As well as complimentary models, complimentary methods will be used across these models to identify the signalling pathways activated by these compounds and their clinical relevance. The patient cells we have in Sheffield have the same mutation as the one introduced in the genetic mouse model; we have already established many of the same mitochondrial abnormalities are present in the patient neurons and both the genetic and toxin induced animal models. Therefore we hypothesise using these models to study the activation pathways of novel compounds will provide excellent, varied scientific training for the PhD student as well as clinically relevant data for Parkinson's Disease to translate laboratory findings to a meaningful clinical outcome.

该项目是来自谢菲尔德大学神经科学系的两名主管、一名工业合作伙伴和来自美国佛罗里达和俄勒冈州的两名合作者之间的合作。该工业合作伙伴已经同意MRC iCase的助学金条款，并发送了一封合作信以确认。该项目建立在帕金森病监督员实验室现有工作的基础上。我们是世界上第一个报告遗传型帕金森病患者外周细胞线粒体功能障碍的研究小组。随后，我们进行了首次使用帕金森病患者细胞的药物筛选，重点是可以提供线粒体改善的化合物。在此之后，主要主管建立了更先进的化合物筛选和补充患者衍生的神经元模型，用于测试前瞻性疗法。在与工业合作伙伴的合作中，我们在患者来源的成纤维细胞和神经元中筛选了约200种新型化合物。基于来自这些测定的数据，已经选择化合物用于帕金森病动物模型中的额外测试。为此，我们开始与两个领先的研究实验室合作，一个是帕金森氏症的遗传小鼠模型;另一个是慢性毒素诱导的帕金森氏症模型。这个博士生项目的目的是充分研究所选化合物在这些帕金森病的免费模型中产生恢复作用的机制。该项目不仅包括在工业合作伙伴的时间，还包括在佛罗里达和俄勒冈州的合作者实验室的时间。这将使学生能够充分研究这些化合物在谢菲尔德（遗传和散发形式）的患者源性神经元中，在遗传小鼠模型和毒素诱导的动物模型中激活的机制途径。除了补充模型外，还将在这些模型中使用补充方法来鉴定这些化合物激活的信号通路及其临床相关性。我们在谢菲尔德的患者细胞具有与遗传小鼠模型中引入的突变相同的突变;我们已经建立了许多相同的线粒体异常存在于患者神经元以及遗传和毒素诱导的动物模型中。因此，我们假设使用这些模型来研究新型化合物的激活途径将为博士生提供出色的，多样化的科学培训以及帕金森病的临床相关数据，以将实验室发现转化为有意义的临床结果。