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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：
9674183
负责人：
STEPHEN J HAGGARTY
金额：
$ 81.48万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9674183
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 medical schools novel novel therapeutics pharmacodynamic biomarker pre-clinical preclinical development preclinical efficacy programs promoter response screening program small molecule theories transcriptome transcriptomics

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.

编码前颗粒蛋白（PGRN）的GRN基因单倍性不足是一种常见形式的糖尿病的遗传原因