Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi

PGRN 调节剂作为额颞叶痴呆新疗法的验证

基本信息

批准号：
10480905
负责人：
STEPHEN J HAGGARTY
金额：
$ 80.09万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480905
关键词：
Address Affect Aging Alleles Alzheimer&apos s Disease Benefits and Risks Binding Biochemical Biological Biological Assay Brain CRISPR/Cas technology Cardiovascular Diseases Cell physiology Cells Cellular Assay Cellular Membrane Cellular biology Chemicals Clinical Collaborations Complex Cultured Cells Dementia Digestion Dose Drug Kinetics Drug Screening Enhancers Epigenetic Process Familial Hypercholesterolemia Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Future GRN gene Gene Expression Gene Expression Profile General Hospitals Generations Genetic Genetic Transcription Genomic approach Glycolipids Glycosphingolipids Golgi Apparatus Heterozygote Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Homeostasis Impairment Individual Inflammation Inflammatory Infusion procedures Institution Isoxazoles Kinetics Knock-out Laboratories Ligands Link Lipids Lysosomal Storage Diseases Lysosomes Massachusetts Measures Membrane Lipids Messenger RNA Metabolic Metabolism Methods Monitor Mus Mutant Strains Mice Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Neurons Nuclear Hormone Receptors Organelles PGRN gene Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Production Property Proteome Proteomics Research Resolution Risk Route Sampling Series Specificity Structure-Activity Relationship Syndrome Techniques Testing Therapeutic Tissues Validation base cellular targeting chromatin modification clinical translation cytokine disorder risk drug discovery extracellular functional genomics gene therapy in vivo in vivo evaluation innovation lipidome lipidomics medical schools novel novel therapeutics pharmacodynamic biomarker pre-clinical preclinical development preclinical efficacy programs promoter response screening program small molecule theories transcriptome transcriptomics translational potential

项目摘要

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.

编码前素蛋白（PGRN）的GRN基因的单倍不足是一种常见形式的遗传原因额颞叶变性（FTLD）引起了独特的额颞痴呆综合征。这是第二种是阿尔茨海默氏病后第二个最常见的痴呆症形式，目前尚无有效的治疗方法两种形式的神经变性。完全缺乏PGRN会导致一种神经元的脂肪促脂肪肌动症形式（NCL），一种溶酶体储存疾病的遗传异质形式，其中细胞的消化膜和糖磷脂受损，从而导致大型损坏的溶酶体积累特别是在神经元中。这一发现已经塑造了我们目前对GRN单倍弥补的理解溶酶体功能障碍的遗传学上不同的潜在形式逐渐减少了“正常” 衰老期间的溶酶体能力。溶酶体功能障碍综合征被认为会诱导产生炎症细胞因子部分通过减少生理脂质配体的生成炎症抑制核激素受体，该受体通过增加小胶质细胞进一步促进神经退行性激活和突触。由GRN单倍不足引起的FTLD提供了独特的治疗途径通过增加其余功能等位基因的基因表达。从理论上讲，基线GRN加倍表达应完全否定受影响个体中这种形式的FTLD的风险。我们的团队有制定了全面的小分子发现策略，导致了几个化学和机械上不同的GRN转录增强子类别。这个项目的目的是为了研究这些小分子对生化和细胞生物学机制的作用 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：目标1优先和优化PGRN增强子，以基于功效的临床前开发来自综合的离体和体内研究的功能特征；目标2确定翻译 PGRN通过评估其标准化细胞和大脑的能力来增强化合物的潜力转录组和脂肪组； AIM 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以及溶酶体脂质组和蛋白质组的影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Active immunotherapy and alternative therapeutic modalities for Alzheimer's disease.

DOI：
10.1002/trc2.12090
发表时间：
2020
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
0
作者：
Weninger S;Sperling B;Alexander R;Ivarsson M;Menzies FM;Powchik P;Weber CJ;Altar CA;Crystal RG;Haggarty SJ;Loring J;Bain LJ;Carrillo MC
通讯作者：
Carrillo MC