Mechanisms of Krabbe Disease Pathobiology and Therapy

克拉伯病病理学和治疗机制

• 批准号: 8643297
• 负责人: Avtar K Singh
• 金额: $ 31.94万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/8643297
• 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

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）是一种发育性神经障碍，其特征是由于β-半乳糖基脑苷酶（GALC）缺乏而导致精神氨酸过度积累以及少突胶质细胞（OL）和髓磷脂的损失。 KD 中 OL 死亡的机制尚不清楚，因此治疗方法一直难以捉摸。本研究旨在研究精神碱诱导 OL 丢失的机制，并鉴定阻止 OL 丢失的药物作为川崎病的潜在疗法。目前的提议是基于我们最初的发现，即精神碱诱导的 OL 细胞凋亡损失是通过 sPLA2 信号通路介导的，并且 sPLA2 抑制剂可以防止 PPAR/过氧化物酶体功能的损失和 OL 的损失。由于用于合成心理素的酶活性的表达对于 OL 分化是不可或缺的，因此描述心理素介导的 OL 分化和丢失机制对于理解 KD 病理学非常重要。基于这些新的发现，我们假设精神嘧啶的积累与 OL 分化的阶段特异性异常有关，并且 sPLA2 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 中的丧失。通过药理学抑制剂对这些途径进行基于机制的干预对于川崎病具有治疗潜力。因此，拟议的研究是； 1) 研究心理素对OLs分化和存活的影响，并阐明心理素介导的OLs分化和存活失调的机制。 2)评价sPLA2抑制剂(DEDA)和抗氧化剂(NAC)对twitcher(TW)小鼠的治疗效果。这些研究基于我们实验室的原始贡献。观察到的 sPLA2 在精神嘧啶诱导的培养物以及 KD/TW 中枢神经系统中 OL 丢失中的作用以及 sPLA2 抑制剂对 OL 丢失的抑制证明了 sPLA2 介导的信号通路在 KD 病理学中的重要性。抑制 sPLA2 信号通路可保护 OL 免受精神毒副作用，这一事实为我们提供了阐明疾病机制并确定 KD 患者潜在治疗方法的机会。对川崎病病理学中这些新的信号传导机制的研究具有创新性，可以将药物确定为川崎病有效治疗的潜在候选药物。