Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi

编码颗粒蛋白前体（PGRN）的GRN基因的单倍不足是一种常见形式的 额颞叶变性（FTLD）引起一种独特的额颞叶痴呆综合征。是 老年痴呆症是仅次于阿尔茨海默氏病的第二种最常见的痴呆症，目前还没有有效的治疗方法。 任何一种形式的神经退化PGRN的完全缺乏导致一种形式的神经元蜡样脂褐质沉积症 (NCL)，一种遗传异质性形式的溶酶体储存病，其中细胞的消化 膜和鞘糖脂受损，导致大的变形溶酶体积聚 尤其是神经元。这一发现塑造了我们目前对GRN单倍不足的理解， 一种遗传上不同的潜在形式的溶酶体功能障碍，加速了“正常”的逐渐减少 衰老过程中的溶酶体能力。溶酶体功能障碍综合征被认为是诱导产生 炎性细胞因子部分通过减少炎症的生理脂质配体的产生 抑制核激素受体，通过增加小胶质细胞，进一步促进神经变性， 激活和突触吞噬。由GRN单倍不足引起的FTLD提供了独特的治疗途径 通过增加剩余功能等位基因的基因表达。从理论上讲， 表达应该完全否定这种形式的FTLD在受影响的个人的风险。我们的团队已被 开发了一种全面的小分子发现策略， 化学上和机械上不同类别的GRN转录增强子。这个项目的目的 是研究这些小分子作用于细胞的生化和细胞生物学机制， GRN基因并优化其特异性和临床前功效。这将通过追求三个 主要目的：目的1根据疗效优先考虑和优化PGRN增强剂用于临床前开发 和功能特征;目的2确定翻译的 通过评价PGRN增强化合物使细胞和脑正常化的能力来评价它们的潜力 目的3确定PGRN增强化合物的翻译潜力 通过研究它们对细胞膜脂质组成和溶酶体脂质组和蛋白质组的影响。

Haploinsufficiency of the GRN gene encoding Progranulin (PGRN) is the genetic cause for a common form of frontotemporal lobar degeneration (FTLD) giving rise to a distinctive frontotemporal dementia syndrome. It is the second most common form of dementia after Alzheimer's disease and currently no effective cure exists for either form of neurodegeneration. Complete lack of PGRN causes a form of neuronal ceroid lipofuscinosis (NCL), a genetically heterogeneous form of lysosomal storage disease in which the digestion of cellular membranes and glycosphingolipids is impaired, resulting in the accumulation of large misshaped lysosomes especially in neurons. This discovery has shaped our current understanding of GRN haploinsufficiency as a genetically distinct latent form of lysosomal dysfunction that accelerates the `normal' progressively diminishing lysosomal capacity during aging. Lysosomal dysfunction syndromes are thought to induce the production of inflammatory cytokines in part through the reduced generation of physiological lipid ligands for inflammation suppressing nuclear hormone receptors, which further promotes neurodegeneration by increasing microglial activation and synaptophagy. FTLD caused by GRN haploinsufficiency offers a unique therapeutic avenue by increasing gene expression from the remaining functional allele. In theory, doubling of baseline GRN expression should completely negate the risk for this form of FTLD in affected individuals. Our team has developed a comprehensive small molecule discovery strategy that has led to the identification of several chemically and mechanistically distinct classes of GRN transcriptional enhancers. The purpose of this project is to investigate the biochemical and cell biological mechanisms through which these small molecules act on the GRN gene and optimize their specificity and preclinical efficacy. This will be achieved by pursuing three major aims: Aim 1 Prioritize and optimize PGRN enhancers for preclinical development based upon efficacy and functional signatures from integrated ex vivo and in vivo studies; Aim 2 Determine the translational potential of PGRN enhancing compounds by evaluating their ability to normalize the cellular and brain transcriptome and lipidome; and Aim 3 Determine the translational potential of PGRN enhancing compounds by investigating their effects on cellular membrane lipid composition and the lysosomal lipidome and proteome.