THE PERIPHERAL NERVOUS SYSTEM: A WINDOW INTO KRABBE DISEASE

周围神经系统：了解克拉伯病的窗口

基本信息

批准号：
10338055
负责人：
M. Laura Feltri
金额：
$ 41.09万
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：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338055
关键词：
3 year old Address Affect Alleles Anatomy Animal Model Autophagocytosis Autophagosome B-Lymphocytes Biochemistry Biological Models Biology Cause of Death Cell Death Cells Cessation of life Data Defect Demyelinating Diseases Demyelinations Deterioration Development Disease Disease model Electron Microscopy Electrophysiology (science)Enzymes Event Galactosylceramides Genes Globoid cell leukodystrophy Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human IGF Type 2 Receptor Immune Immunohistochemistry Impairment Infant Infiltration Inflammation Life Lipids LoxP-flanked allele Lysosomal Storage Diseases Lysosomes Measures Membrane Messenger RNA Morphology Motor Motor Neurons Mus Mutation Myelin Neonatal Mortality Nerve Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Null Lymphocytes Optics Pathogenesis Pathology Patients Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Property Proteins Proteome Psychosine Quality of life Recombinants Reporter Role Schwann Cells Sensory Site Source Testing Tissues Toxic effect axonal degeneration base cell type cytotoxic design galactosylceramidase gene therapy improved in vivo macrophage mutant nervous system disorder neuroinflammation recruit stem cell therapy stem cells symptomatic improvement uptake

项目摘要

Krabbe leukodystrophy (KD) or Globoid Cell Leukodystrophy is a severe lysosomal storage disorder that mainly affects infants in the first months of life and is usually fatal within a couple of years. KD presents with irritability and motor deterioration, which progresses to overall decline and death due to demyelination and neurodegeneration in the central and peripheral nervous system (CNS and PNS). KD is due to recessive mutations in galactosylceramidase (GALC) a lysosomal enzyme that catabolizes the major myelin lipid galactosylceramide and the cytotoxic lipid psychosine. Psychosine accumulates in patients and is toxic to myelinating glia and neurons causing demyelination and neurodegeneration (psychosine hypothesis). Although myelin is affected in KD, GALC is present in all cell types and other cells, such as neurons and macrophages, may be important and involved early in the disease. There is no cure for KD, but Hematopoietic stem cell transplantation (HSCT) improves symptoms presumably by cross-correction: the uptake by mutant cells of GALC secreted by stem cell-derivatives. Patients who receive HSCT eventually deteriorate, possibly due to insufficient PNS cross-correction. This has not been evaluated experimentally and in general the PNS is emerging as an important KD component that is not targeted by available therapies. The Twitcher mouse is a spontaneous model of the disease that has been used extensively and recently used to show that HSCT, substrate reduction and gene therapy have synergistic beneficial effects, suggesting multiple disease mechanisms. Despite these advancements, many fundamental aspects of KD pathogenesis are still unknown. For example, are KD neurons and macrophages involved in a cell autonomous manner? Is cross- correction efficient and does it occur in all cell types in vivo? Do all cells produce psychosine, or only certain cell types? Besides psychosine toxicity, are other mechanisms involved? We recently developed a conditional Galc allele and have deleted Galc in various cell types in the CNS and PNS. In this proposal, we will use the PNS, due to its relative simplicity and anatomical isolation, to answer the fundamental questions raised above. Based on a strong set of preliminary data, we postulate that cross- correction does not occur efficiently in vivo, that myelinating glia produce psychosine, and that deleting GALC has a cell autonomous effect in each cell type, likely by perturbing lysosomal function and autophagy. Our results will reveal fundamental aspects of PNS biology and help to understand the pathomechanisms of KD and the limitations of HSCT, which will allow the development of better therapies for KD and other lysosomal, neurodegenerative and demyelinating diseases.

克拉伯脑白质营养不良 (KD) 或球状细胞脑白质营养不良是一种严重的溶酶体贮积病这种疾病主要影响出生后头几个月的婴儿，通常在几年内致命。川崎病表现为烦躁和运动能力恶化，进而导致整体衰退和死亡中枢和周围神经系统（CNS 和 PNS）的脱髓鞘和神经变性。 KD 是由于半乳糖神经酰胺酶 (GALC) 的隐性突变所致，半乳糖神经酰胺酶是一种溶酶体酶，可分解代谢主要的髓磷脂脂质半乳糖神经酰胺和细胞毒性脂质精神氨酸。心衰累积对患者有髓鞘神经胶质和神经元毒性，导致脱髓鞘和神经变性（精神碱假说）。尽管髓鞘质在 KD 中受到影响，但 GALC 存在于所有细胞类型和其他细胞中细胞，例如神经元和巨噬细胞，可能很重要并参与疾病的早期。有川崎病无法治愈，但造血干细胞移植 (HSCT) 可能会通过以下方式改善症状：交叉校正：突变细胞对干细胞衍生物分泌的 GALC 的摄取。患者谁接受 HSCT 最终恶化，可能是由于 PNS 交叉校正不足。这还没有经过实验评估，总的来说，PNS 正在成为 KD 的一个重要组成部分，不是现有疗法的目标。 Twitcher 小鼠是这种疾病的自发模型已被广泛使用，最近用于表明 HSCT、底物减少和基因治疗具有协同有益作用，提示多种疾病机制。尽管取得了这些进展，川崎病发病机制的许多基本方面仍然未知。例如，KD 神经元和巨噬细胞是否以细胞自主方式参与？是跨校正效率高吗？它是否发生在体内所有细胞类型中？所有细胞都产生精神嘧啶吗？还是只产生精神嘧啶？某些细胞类型？除了精神毒性之外，是否还涉及其他机制？我们最近开发了条件性 Galc 等位基因，并在 CNS 和 PNS 的各种细胞类型中删除了 Galc。在这个提案中，我们将使用 PNS，因为它相对简单且解剖学隔离，来回答上面提出的基本问题。基于一组强有力的初步数据，我们假设跨校正在体内并没有有效地发生，髓鞘神经胶质细胞产生精神碱，并且删除 GALC 在每种细胞类型中都具有细胞自主效应，可能是通过扰乱溶酶体功能和自噬。我们的结果将揭示 PNS 生物学的基本方面，并有助于理解 KD 的发病机制和 HSCT 的局限性，这将有助于开发更好的川崎病和其他溶酶体、神经退行性和脱髓鞘疾病的治疗。