Cell Specific Ablation of GALC and the Pathogenesis of Krabbe Disease

GALC 的细胞特异性消融与克拉伯病的发病机制

基本信息

批准号：
9191994
负责人：
Nadav Weinstock
金额：
$ 2.83万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-11 至 2020-07-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191994
关键词：
Ablation Address Affect Age Autonomic Dysfunction Behavioral Brain Cell Death Cells Cessation of life Clinical Cranial Nerves Data Demyelinating Diseases Demyelinations Development Disease Disease Progression Early Intervention Electron Microscopy Electrophysiology (science)Enzymes Fibroblasts Functional disorder Future Galactosylceramides Genes Globoid cell leukodystrophy Goals Hematopoietic Stem Cell Transplantation High Pressure Liquid Chromatography Human Impaired cognition Impairment In Situ Nick-End Labeling In Vitro Infant Infantile Globoid Cell Leukodystrophy Knockout Mice Length Life Lipids LoxP-flanked allele Measures Microtomy Midbrain structure Molecular Morphology Motor Mus Mutation Myelin Nerve Degeneration Neuraxis Neurites Neuroglia Neurologic Neurons Oligodendroglia Organ Pathogenesis Pathology Patients Peripheral Peripheral Nervous System Phenotype Pluripotent Stem Cells Procedures Production Psychosine Research Role Schwann Cells Severities Severity of illness Spinal Cord Staining method Stains Sudden Death Symptoms Synapsins Testing Therapeutic Toxic effect Varicosity Walking afferent nerve autonomic nerve axonal degeneration cytotoxic dopaminergic neuron galactosylceramidase infancy leukodystrophy loss of function mouse model myelination nerve conduction study nervous system disorder neurodegenerative phenotype neuron apoptosis novel research study retinal rods

项目摘要

Krabbe Disease (KD) is a rare neurologic disease characterized by progressive demyelination in the central and peripheral nervous systems (CNS and PNS, respectively). KD typically affects infants in the first few months of life and quickly progresses to overall clinical decline and death within months. The only available treatment for KD is Hematopoietic Stem Cell Transplantation (HSCT), which has limited therapeutic applications as it must be administered before the onset of symptoms occur, and unfortunately has partial long term efficacy despite early intervention. KD is due to inheritable mutations in the GALC gene leading to a loss- of-function in the lysosomal enzyme galactosylceramidase (GalC), responsible for the degradation of galactosylceramide and a structurally related metabolite known as psychosine. Psychosine accumulates in patients with KD and is thought to be responsible for the death of myelin forming cells in the CNS (oligodendrocytes) and PNS (Schwann cells). Recent data suggest that psychosine toxicity in KD may also target neurons primarily, causing axonal and neuronal degeneration even before and independent of demyelination. It is also hypothesized that limitations of HSCT in KD patients may be due to a limited restorative effect of myelination in the PNS, which may cause severe weakness and autonomic dysfunction leading to sudden death. However, the extent of the contribution of PNS pathology to symptoms in KD has not been determined. Similarly, the primary role of KD on neurons, independent of demyelination, has not been determined. To investigate the role of cell autonomy in KD, this project will use a conditional deletion strategy in mice to specifically ablate GalC function in Schwann cells or neurons, independently. These mice will then be evaluated and characterized for disease progression by clinical, electrophysiological, pathological and molecular measures. Additionally, we will study neurons derived from fibroblasts from KD patients, in vitro, to determine if KD neurons are inherently susceptible to pathology. Our data will provide information on the interplay between glia and neurons in neurodegeneration, a central emerging question in most neurological diseases, including the leukodystrophies. In addition, findings from this proposal will help to understand the disease mechanisms of KD and the limitations of HSCT, which will allow us to develop better therapies for KD and similar demyelinating diseases in the future.

克拉伯病 (KD) 是一种罕见的神经系统疾病，其特征是中枢神经系统和周围神经系统（分别为 CNS 和 PNS）进行性脱髓鞘。川崎病通常会影响出生后最初几个月的婴儿，并在几个月内迅速进展为整体临床衰退和死亡。川崎病唯一可用的治疗方法是造血干细胞移植（HSCT），其治疗应用有限，因为它必须在症状出现之前进行，不幸的是，尽管早期干预，但仍具有部分长期疗效。 KD 是由于 GALC 基因的遗传性突变导致溶酶体酶半乳糖神经酰胺酶 (GalC) 功能丧失，该酶负责半乳糖神经酰胺和一种结构相关的代谢物（称为精神氨酸）的降解。心苷在川崎病患者体内积聚，被认为是中枢神经系统（少突胶质细胞）和三七总皂甙细胞（雪旺细胞）中髓磷脂形成细胞死亡的原因。最近的数据表明，川崎病中的精神碱毒性也可能主要针对神经元，甚至在脱髓鞘之前就引起轴突和神经元变性，并且与脱髓鞘无关。还假设 KD 患者 HSCT 的局限性可能是由于 PNS 髓鞘形成的恢复作用有限，这可能导致严重虚弱和自主神经功能障碍，导致猝死。然而，PNS 病理学对川崎病症状的影响程度尚未确定。同样，KD 对神经元的主要作用（与脱髓鞘无关）尚未确定。为了研究细胞自主性在 KD 中的作用，该项目将在小鼠中使用条件删除策略，以独立地特异性消除雪旺细胞或神经元中的 GalC 功能。然后将通过临床、电生理学、病理学和分子测量来评估和表征这些小鼠的疾病进展。此外，我们将在体外研究来自川崎病患者成纤维细胞的神经元，以确定川崎病神经元是否天生易受病理影响。我们的数据将提供有关神经变性中神经胶质细胞和神经元之间相互作用的信息，神经变性是大多数神经系统疾病（包括脑白质营养不良）中出现的一个核心问题。此外，该提案的研究结果将有助于了解川崎病的发病机制和造血干细胞移植的局限性，这将使我们能够在未来开发出更好的治疗川崎病和类似脱髓鞘疾病的疗法。