Conditional Models: Non-cell-antonomous Toxicities in HD

描述(申请人提供)：神经退行性疾病的发病机制中的一个共同主题是，广泛表达的突变蛋白可以导致大脑中神经元的子集选择性退化。在大多数情况下，这种选择性神经变性背后的分子和细胞机制尚不清楚。以亨廷顿病(HD)为模型，我们将研究HD中纹状体和皮质神经元的选择性变性是否需要来自这些神经元外部的突变红丁素(MHT)毒性(非细胞自主毒性)。在我们的初步研究中，我们开发了两种条件小鼠模型，在这些模型中，MHT的表达可以在特定的神经元群体中激活或失活。我们建议使用这些小鼠模型来实现以下三个特定目的：具体目的1.对皮质激活小鼠模型和全脑激活小鼠模型进行表型分析，以确定非细胞自主毒性是否与脆弱的皮质和纹状体神经元的功能障碍和退化有关。具体目的2.纹状体激活小鼠模型的表型分析，以确定非细胞自主毒性是否与纹状体和皮质神经元的功能障碍和退化有关。具体目的3.建立全长MHT皮质失活小鼠模型，以研究非细胞自主毒性是否在全长MHT小鼠模型的疾病发病机制中所需。综上所述，我们建议使用一系列新的条件小鼠HD模型来研究神经元回路在HD发病机制中的作用。我们的研究可能揭示，MHT毒性来自最脆弱的神经元之外，可能是其功能障碍和退化所必需的。这种毒性的确定将对开发HD和其他神经退行性疾病的治疗方法具有重要意义。

DESCRIPTION (provided by applicant): A common theme in the pathogenesis of the neurodegenerative diseases is that a widely expressed mutant protein can cause selective degeneration of a subset of neurons in the brain. In most of the cases, the molecular and cellular mechanisms underlying such selective neurodegeneration remain unclear. Using Huntington's disease (HD) as a model, we will investigate whether selective degeneration of the striatal and cortical neurons in HD requires mutant Hungtingtin (mHt) toxicities originated from outside these neurons (non-cell-autonomous toxicities). In our preliminary studies, we have developed two conditional mouse models in which mHt expression can either be activated or inactivated in specific neuronal populations. We propose to use these mouse models to achieve the following three Specific Aims: Specific Aim 1. Phenotypic analyses of the cortical activation mouse model and the whole brain activation mouse model to determine whether non-cell autonomous toxicities are involved in dysfunction and degeneration of the vulnerable cortical and striatal neurons. Specific Aim 2. Phenotypic analyses of the striatal activation mouse model to determine if the non-cellautonomous toxicities are involved in dysfunction and degeneration of the striatal and cortical neurons. Specific Aim 3. Generation of a full length mHt cortical-inactivation mouse model to study whether non-cell autonomous toxicities are required in disease pathogenesis in a full length mHt mouse model. In summary, we propose to use a novel series of conditional mouse models of HD to study the role of neuronal circuitry in HD pathogenesis. Our studies may reveal that mHt toxicities originated from outside the most vulnerable neurons may be required for their dysfunction and degeneration. Identification of such toxicities will have important implications for developing therapeutics for HD as well as for other neurodegenerative diseases.