Animal Models for Studying Human Frontotemporal Dementia

描述（由申请人提供）：内体-溶酶体途径的缺陷与几种神经退行性疾病有关，但详细的潜在分子机制在很大程度上仍然未知。额颞叶变性（FTLD）是一种与额叶和/或颞叶局灶性萎缩相关的进行性神经退行性疾病。FTLD是早老性痴呆最常见的形式之一。越来越多的临床和分子证据表明，FTLD和肌萎缩侧索硬化症有许多共同的致病机制。事实上，几个基因，包括CHMP 2B，VCP，TDP-43，FUS，Ubiquilin 2和C9 ORF 72，都与这两种疾病的分子发病机制有关。在R 01资助的第一个资助周期中，我们建立了神经元细胞模型和突变CHMP 2B毒性的果蝇模型，并研究了ESCRT和自噬在神经变性中的作用。为了更紧密地模拟人类疾病，我们建立了一种新的转基因小鼠模型，该模型表现出FTLD相关神经变性的几个关键特征。在这项更新申请中，我们建议进行分子，细胞，遗传和行为分析，以进一步表征这种新型FTLD小鼠模型，目的是获得体内致病事件的机制见解。拟议的研究将显着提高我们对FTLD疾病机制的理解，并可能揭示治疗干预的新靶点。

DESCRIPTION (provided by applicant): Defects in the endosomal-lysosomal pathway have been implicated in several neurodegenerative diseases but the detailed underlying molecular mechanisms remain largely unknown. Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. FTLD is one of the most common forms of presenile dementia. Increasing clinical and molecular evidence indicates that FTLD and amyotrophic lateral sclerosis share many common pathogenic mechanisms. Indeed, several genes, including CHMP2B, VCP, TDP-43, FUS, Ubiquilin 2, and C9ORF72, have been implicated in the molecular pathogenesis of both diseases. During the first funding cycle of this R01 grant, we established a neuronal cell model and a Drosophila model of mutant CHMP2B toxicity and investigated the roles of ESCRTs and autophagy in neurodegeneration. To more closely model human disease, we established a novel transgenic mouse model that exhibits several key features of FTLD-associated neurodegeneration. In this renewal application, we propose to carry out molecular, cellular, genetic, and behavioral analyses to further characterize this novel mouse model of FTLD, with the goal of gaining mechanistic insights into pathogenic events in vivo. The proposed studies will significantly enhance our understanding of disease mechanisms in FTLD and may reveal novel targets for therapeutic interventions.