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New approach for cholesterol and sphingolipid reduction in Niemann-Pick C1 disease

降低尼曼-匹克 C1 病胆固醇和鞘脂的新方法

基本信息

批准号：
10078545
负责人：
Jason Charles Newton
金额：
$ 16.55万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-25 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078545
关键词：
Address Agreement Autophagocytosis Behavioral Symptoms Binding Brain CRISPR/Cas technology Catabolism Cells Cerebellum Child Childhood Cholesterol Clinical Trials Cognition Combined Modality Therapy Complex Data Defect Development Disease Disease Progression Dose Enzymes Epigenetic Process Fibroblasts Functional disorder Genes Goals Histone Deacetylase Histone Deacetylase Inhibitor Homeostasis Human Knowledge Life Extension Life Support Care Lipids Liver Longevity Lysosomes Mediating Mediator of activation protein Membrane Memory Mentors Metabolic Pathway Metabolism Molecular Molecular Genetics Monitor Motor Skills Movement Mus Mutant Strains Mice Mutation NPC1 gene National Institute of Child Health and Human Development Nerve Degeneration Neurologic Nuclear Pathogenesis Pathogenicity Pathology Patients Pharmacology Phase Phenotype Play Process Proteins Publishing Regulation Research Role SPHK1 enzyme Sphingolipids Sphingosine Supraoptic Vertical Ophthalmoplegia System Techniques Therapeutic Training Work base cholesterol trafficking citrate carrier clinically relevant disease-causing mutation effective therapy human disease improved outcome in vivo innovation late endosome liver function mouse model multiple sclerosis treatment mutant mutant mouse model neuroinflammation neuropathology novel novel strategies novel therapeutic intervention overexpression programs progressive neurodegeneration restoration sphingosine 1-phosphate sphingosine kinase targeted treatment therapeutic evaluation trafficking treatment strategy

项目摘要

Niemann-Pick Type C (NPC) is fatal lipid storage disease caused by mutations in NPC1 (95%) and NPC2 (5%) genes. NPC is characterized by cholesterol and sphingolipid accumulation, complex progressive neurodegeneration, and a lifespan of less than 20 years. NPC1/2 function in late endosomes/lysosomes (LE/L), with soluble NPC2 binding unesterified cholesterol and transferring it to integral membrane NPC1 that facilitates its movement out of the LE/L. Recently it was discovered that HDAC inhibition can epigenetically increase expression of the low activity NPC1mut protein to levels that can correct the cholesterol defect. However, HDAC inhibitors now being tried for treatment NPC do not get into the CNS and do not treat the neurological sequelea of NPC. My published results, however, suggest that FTY720/Fingolimod, used for treatment of multiple sclerosis, is also a HDAC inhibitor that increases expression of NPC1/2 and corrects cholesterol and sphingolipid storage defects in NPC1mut fibroblasts. Furthermore, my preliminary data in mice show that FTY720 does accumulate in the cerebellum, increases NPC1/2 expression in brain as well as liver, and reduces cholesterol levels. Hence, in my first Aim, I will extend this approach to an in vivo mouse model of NPC that more accurately mimics the human disorder, monitoring brain and liver NPC1/2 expression, cholesterol and sphingolipid homeostasis, and disease progression. While accumulation of sphingolipids have been implicated in development of NPC-associated neurological defects, the mechanisms remain unknown. Recent published work and my preliminary data support the premise that a deficiency of sphingosine kinase 1 (SphK1), which converts the sphingolipid metabolite sphingosine to the bioactive mediator sphingosine-1- phosphate, may be important in pathogenesis of NPC. Consequently, my Aim 2a focuses on the role of SphK1 in sphingolipid accumulation on a cellular level through a detailed examination of its expression, localization, and regulation in NPC mutant fibroblasts. Furthermore, by employing a novel SphK1 activator we recently discovered, and CRISPR CAS9 mediated modulation of SphK1 expression and activity, I will examine whether increasing sphingolipid catabolism suppresses the NPC cellular phenotype. Finally, most therapeutic approaches focus on reducing cholesterol accumulation, but our preliminary data suggest that cholesterol and sphingolipid metabolic pathways are interdependent, decreased SphK1 activity leads to accumulation of both sphingolipids and cholesterol. Therefore, I will examine the benefits of targeting both cholesterol and sphingolipid accumulation through a novel “dual lipid” reduction strategy in a mouse model of NPC. I expect that my results will validate the use of FTY720/Fingolimod to effectively restore normal NPC1/2 activity levels, answer longstanding questions about the mechanism of sphingolipid accumulation in NPC, and pave the way for a new therapeutic strategy targeting both pathogenic classes of lipids in NPC disease.

尼曼-皮克C型（NPC）是由NPC1（95%）和NPC2（5%）突变引起的致命性脂质储存疾病。