SSA: Analysis of Gene Interactions in Neurodegeneration

纹状体是前脑基底节的重要组成部分。它的重要作用之一是控制自愿行动。其主要神经元类型为中棘神经元(MSN)，在进行性神经退行性疾病亨廷顿病(HD)中变性。导致突变的原因是亨廷顿(Htt)基因的“CAG重复”扩大。重要的是，HD被确立为更广泛地理解神经退行性变的范例。了解在正常脑发育过程中产生MSN的分子机制以及突变型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，它们都是产生HD新疗法的关键(目前还没有改善疾病的疗法可用)。一种既定的进展方法是使用模型生物体作为体内系统进行所需的机械分析。鼠标是MSN研究中最受欢迎的模型。我们利用它来研究在脑发育过程中产生MSN的细胞分化途径，并已经鉴定出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，Mef2D(与MEF2C密切相关)和FoxP1都被报道能抑制mHTT诱导的果蝇模型中的神经变性。这表明这些转录因子不仅与发育途径有关，而且还与神经退行性变有关。为了探索这些新的发现，你将使用遗传学和神经科学的不同技术。对经典模式生物果蝇进行体内遗传分析，凭借其复杂的技术范围，提供快速洞察，具有许多优势。您将使用果蝇通过有效地测试假设来补充小鼠。只有最有可能提供信息的分析才会被带到老鼠那里，因为老鼠与人类生物学有更密切的联系，但在那里进行实验需要更长的时间。你将用果蝇的眼睛作为体内的“试管”来分析哺乳动物在神经退化中的基因功能。它为这种现象提供了一个简单的读数。你将使用遗传工具来驱动mHTT在眼睛中的表达，以诱导神经退化，然后测试这一过程的遗传修饰物。初步结果将指导后续的机械分析。你们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。你将通过行为分析和免疫组织化学对神经元包涵体和MSN标记进行评估，然后测试候选基因上调或下调对这种神经退行性变表型的影响。

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.