Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi

编码原颗粒蛋白(PGRN)的GRN基因单倍性不足是一种常见形式的 额颞叶变性(FTLD)导致一种独特的额颞叶痴呆综合征。它是 仅次于阿尔茨海默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变性。PGRN的完全缺乏导致一种形式的神经元蜡样脂褐素沉着症 (NCL)，一种遗传异质性的溶酶体储存疾病，在这种疾病中细胞的消化 膜和神经鞘糖脂受损，导致大的畸形溶酶体堆积。 尤其是在神经元中。这一发现形成了我们目前对GRN单倍体功能不全的理解 基因上截然不同的溶酶体功能障碍的潜伏期，加速了“正常”的渐进性消退 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生理性脂质配体的生成来促进炎症 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。GRN单倍体功能不全引起的FTLD提供了一种独特的治疗途径 通过增加剩余功能等位基因的基因表达。从理论上讲，基线GRN翻一番 在受影响的个体中，表达应该完全否定这种形式的FTLD的风险。我们队有 开发了一种全面的小分子发现战略，该战略已经导致确定了几个 化学和机械上不同类别的GRN转录增强子。这个项目的目的是 是研究这些小分子作用的生化和细胞生物学机制 并优化其特异性和临床前疗效。这将通过追求三个目标来实现 主要目标：目标1根据疗效确定和优化临床前开发的PGRN增强剂的优先顺序 和来自整合的体外和体内研究的功能特征；目标2确定翻译 通过评估PGRN化合物使细胞和大脑正常化的能力来增强其潜力 转录组和脂体；以及目标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体和蛋白质组的影响。

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.