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Mechanisms of Krabbe Disease Pathobiology and Therapy

克拉伯病病理学和治疗机制

基本信息

批准号：
8448639
负责人：
Avtar K Singh
金额：
$ 31.14万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448639
关键词：
Abbreviations Acetone Acetylcysteine Acids Acyltransferase Affect Antioxidants Apoptosis Apoptotic Astrocytes Brain Cell Death Cells Ceramides Cessation of life Complement Cycloserine Data Development Disease Functional disorder Galactolipids Galactosylceramides Genetic Globoid cell leukodystrophy Health In Vitro Infant Intervention Knockout Mice Laboratories Longevity Mediating Morbidity - disease rate Mus Myelin Myelin Basic Proteins Normal Cell Oligodendroglia Oxidative Stress PDGFRB gene Pathology Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phospholipase A2 Platelet-Derived Growth Factor Receptor Proliferating Proteins Proteolipids Psychosine RNA RNA Interference Reactive Oxygen Species Role Seminal Signal Pathway Signal Transduction Sphingosine Staging Stem cells Subfamily lentivirinae Sulfoglycosphingolipids Testing Therapeutic Tissues Toxic effect Transferase Treatment Efficacy Uridine Diphosphate Galactose Wild Type Mouse attenuation base design dysmyelination effective therapy galactosylceramidase inhibitor/antagonist innovation inorganic phosphate loss of function myelination nervous system disorder novel peroxisome prevent progenitor public health relevance relating to nervous system response therapeutic target time interval

项目摘要

DESCRIPTION (provided by applicant): Krabbe disease (KD) is a developmental neurological disorder characterized by excessive accumulation of psychosine and loss of oligodendrocytes (OLs) and myelin as a result of deficiency of ¿-galactosylcerebrosidase (GALC). Mechanisms of OL death in KD are not well understood, and thus therapy has been elusive. This study is designed to investigate the psychosine induced mechanism of OL loss and the identification of drugs that block the loss of OLs as potential therapy for KD. The present proposal is based on our original findings that psychosine-induced apoptotic loss of OLs is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 protect against loss of PPAR/peroxisomal functions and loss of OLs. Since the expression of enzymatic activity for synthesis of psychosine is integral to OL differentiation, delineation of psychosine mediated mechanisms in differentiation and loss of OLs is important for understanding KD pathology. Based on these novel findings, we hypothesize that the accumulation of psychosine is associated with stage(s) specific abnormalities in OL differentiation and that activation of sPLA2 and inhibition of PPAR/ peroxisomal functions participate in dysregulation of OL differentiation and their loss in KD. Mechanism based interventions of these pathways by means of pharmacological inhibitors have therapeutic potential in KD. Therefore, the proposed studies are; 1) To investigate the effects of psychosine on differentiation and survival of OLs and to elucidate the mechanisms of psychosine-mediated dysregulation of OLs differentiation and survival. 2) To evaluate the therapeutic efficacy of inhibitor of sPLA2 (DEDA) and antioxidant (NAC) for the treatment of twitcher (TW) mice. These studies are based on the original contributions from our laboratory. The observed role of sPLA2 in psychosine induced loss of OLs in culture as well as in CNS of KD/TW and inhibition of OLs loss by sPLA2 inhibitor documents the significance of sPLA2 mediated signaling pathways in KD pathology. The fact that inhibition of sPLA2 signaling pathway protects OLs against psychosine toxicity provides us an opportunity to elucidate disease mechanisms and to identify potential therapeutics for patients with KD. Study of these novel signaling mechanisms in KD pathology are innovative and may identify drug(s) as potential candidates for effective therapy for KD.

描述（由申请人提供）：克拉伯病（KD）是一种发育性神经系统疾病，其特征是由于半乳糖苷脂酶（GALC）缺乏导致的精神病碱过度蓄积和少突胶质细胞（OL）和髓鞘丢失。KD中OL死亡的机制尚不清楚，因此治疗一直难以捉摸。本研究旨在探讨精神碱诱导OL丢失的机制，并鉴定阻断OL丢失的药物作为KD的潜在治疗方法。目前的建议是基于我们最初的发现，即精神分裂素诱导的OL凋亡损失是通过sPLA 2信号通路介导的，并且sPLA 2抑制剂可以防止PPAR/过氧化物酶体功能的损失和OL的损失。由于用于合成Psychosine的酶活性的表达是OL分化的组成部分，因此描绘Psychosine介导的OL分化和损失机制对于理解KD病理学是重要的。基于这些新的发现，我们假设精神病碱的积累与OL分化中的阶段特异性异常相关，并且sPLA 2的激活和PPAR/过氧化物酶体功能的抑制参与了OL分化的失调及其在KD中的损失。通过药理学抑制剂对这些途径进行基于机制的干预，对KD具有治疗潜力。因此，本研究拟从以下几个方面进行研究：1）研究精神碱对OLs分化和存活的影响，阐明精神碱介导的OLs分化和存活失调的机制。2)探讨sPLA 2抑制剂（DEDA）和抗氧化剂（NAC）对抽动症（TW）小鼠的治疗作用。这些研究是基于我们实验室的原始贡献。在KD/TW的培养物以及CNS中观察到的sPLA 2在精神病碱诱导的OL损失中的作用以及sPLA 2抑制剂对OL损失的抑制证明了sPLA 2介导的信号传导途径在KD病理学中的重要性。抑制sPLA 2信号通路保护OL免受精神碱毒性的事实为我们提供了阐明疾病机制和鉴定KD患者的潜在治疗剂的机会。KD病理学中这些新的信号传导机制的研究是创新的，并且可以鉴定药物作为KD有效治疗的潜在候选物。