SSA: Analysis of Gene Interactions in Neurodegeneration

SSA：神经退行性变中基因相互作用的分析

• 批准号: 2437287
• 金额: --
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2437287
• 关键词: SSA; Analysis; Gene; Interactions; Neurodegeneration

The striatum is a key component of the basal ganglia in the forebrain. One of its important roles is in the control of voluntary movement. Its principle neuronal type, the medium spiny neuron (MSN) degenerates in the progressive neurodegenerative condition Huntington's Disease (HD). The causal mutation is expansion of the "CAG repeat" of the Huntingtin (Htt) gene. Importantly, HD is established as a paradigm for understanding neurodegeneration more generally. Understanding the molecular mechanism that produce MSNs in normal brain development and the mechanisms by which mutant Htt (mHtt) leads to MSN degeneration are important questions in neuroscience. In the longer term, they are both critical to producing new treatments for HD (no disease modifying treatments are currently available). An established approach for progress is to use model organisms as an in vivo system for the required mechanistic analysis. The mouse is a favoured model for MSN research. We use it to investigate the cell differentiation pathway that produces MSNs during brain development and have identified two transcription factor-encoding genes, Mef2C and FoxP1, required for normal striatal MSN development. Intriguingly, both Mef2D (closely related to Mef2C) and FoxP1 are reported to suppress mHtt-induced neurodegeneration in a Drosophila model. This implicates these transcription factors not only in the developmental pathways, but also in rescue of neurodegeneration.To explore these novel findings, you will use diverse techniques from genetics and neurosciences. In vivo genetic analysis in the classic model organism, Drosophila, has many advantages with its sophisticated range of techniques that give rapid insight. You will use Drosophila to complement the mouse by efficiently testing hypotheses. Only analyses most likely to be informative will be brought to the mouse, which has closer links to human biology, but where experiments take much longer. You will use the Drosophila eye as an in vivo "test tube" to analyse mammalian gene function in neurodegeneration. It provides a simple readout of this phenomenon. You will use genetic tools to drive expression of mHtt in the eye to induce neurodegeneration and then test genetic modifiers of this process. Initial results will guide subsequent mechanistic analysis. Your complementary experiments will use a mouse model that expresses mHtt and produces a mild HD-like phenotype. You will assess this with a behavioural assay and immuno-histochemistry for neuronal inclusions and MSN markers, and then test effects of up- or down-regulation of candidate genes on this neurodegeneration phenotype.

纹状体是前脑基底神经节的重要组成部分。它的重要作用之一是控制自主运动。其主要的神经元类型，中棘神经元（MSN）在进行性神经退行性疾病亨廷顿氏病（HD）中变性。导致突变的原因是亨廷顿蛋白（Htt）基因的CAG重复扩增。重要的是，HD被确立为更普遍地理解神经退行性变的范例。了解正常脑发育过程中产生MSN的分子机制以及突变Htt （mHtt）导致MSN变性的机制是神经科学中的重要问题。从长远来看，它们都是生产HD新疗法的关键（目前还没有可以改变疾病的疗法）。一种成熟的方法是使用模式生物作为体内系统进行所需的机制分析。鼠标是MSN研究的首选模型。我们用它来研究大脑发育过程中产生MSN的细胞分化途径，并发现了两个转录因子编码基因，Mef2C和FoxP1，它们是正常纹状体MSN发育所必需的。有趣的是，在果蝇模型中，Mef2D（与Mef2C密切相关）和FoxP1都被报道抑制mhttt诱导的神经变性。这暗示这些转录因子不仅在发育途径中，而且在神经退行性变的救援中。为了探索这些新发现，你将使用遗传学和神经科学的各种技术。在体内遗传分析的经典模式生物，果蝇，具有许多优势，其复杂的技术范围，给快速洞察。你将使用果蝇来补充小鼠，有效地测试假设。只有最有可能提供信息的分析才会被带到老鼠身上，老鼠与人类生物学有更密切的联系，但实验需要更长的时间。你将使用果蝇的眼睛作为体内的“试管”来分析哺乳动物在神经变性中的基因功能。它提供了对这种现象的简单解读。您将使用遗传工具来驱动mHtt在眼睛中的表达，以诱导神经变性，然后测试这一过程的遗传修饰剂。初步结果将指导后续的机理分析。您的补充实验将使用表达mHtt并产生轻度hd样表型的小鼠模型。您将通过行为测定和神经元包涵体和MSN标记物的免疫组织化学来评估这一点，然后测试候选基因上调或下调对这种神经变性表型的影响。