Mechanisms of Krabbe Disease Pathobiology and Therapy

克拉伯病病理学和治疗机制

• 批准号: 8109021
• 负责人: Avtar K Singh
• 金额: $ 32.27万
• 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/8109021
• 关键词: Acetylcysteine; Acids; Affect; Antioxidants; Apoptosis; Apoptotic; Astrocytes; Brain; Cell Death; Cells; 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; Normal Cell; Oligodendroglia; Oxidative Stress; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phospholipase A2; Proliferating; Psychosine; Role; Seminal; Signal Pathway; Signal Transduction; Sphingosine; Staging; Sulfoglycosphingolipids; Testing; Therapeutic; Tissues; Toxic effect; Transferase; Treatment Efficacy; Uridine Diphosphate Galactose; attenuation; base; design; dysmyelination; effective therapy; inhibitor/antagonist; innovation; loss of function; myelination; nervous system disorder; novel; peroxisome; prevent; progenitor; 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. PUBLIC HEALTH RELEVANCE: Pathognomic accumulation of psychosine and psychosine-induced impaired myelination and loss of oligodendrocytes and myelin are the "hallmark" of Krabbe disease. This proposal is to evaluate the efficacy of inhibitors of sPLA2 signaling pathway to delineate disease mechanisms and to identify potential therapeutics 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，其特征是精神氨酸过度积累以及由于 ¿ 缺乏而导致少突胶质细胞 (OL) 和髓鞘质丧失。 -半乳糖脑苷脂酶 (GALC) 导致 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氨酸诱导的 OL 丢失机制，并鉴定可能阻止 OL 丢失的药物。目前的建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，并且抑制剂sPLA2 的作用可防止 PPAR/过氧化物酶体功能的丧失和 OL 的丧失，因为精神碱合成酶活性的表达是 OL 分化的组成部分，因此描述精神碱介导的 OL 分化和丧失机制对于理解基于 KD 的病理学非常重要。根据这些新发现，我们发现，精神嘧啶的积累与 OL 分化阶段的特异性异常有关，并且 sPLA2 的激活和 PPAR/PPAR/ 的抑制有关。过氧化物酶体功能参与 KD 中 OL 分化及其丧失的机制，通过药物抑制剂对这些途径进行干预具有治疗 KD 的潜力。 OLs 并阐明精神碱介导的 OLs 分化和存活失调的机制 2) 评估 sPLA2 抑制剂 (DEDA) 和抗氧化剂 (NAC) 的治疗效果。这些研究基于我们实验室观察到的 sPLA2 在培养物中诱导 OL 丢失以及 KD/TW 中枢神经系统中 OL 丢失的作用以及通过抑制 OL 丢失的原始贡献。 sPLA2 抑制剂记录了 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一个机会。阐明疾病机制并确定川崎病患者的潜在治疗方法 对川崎病病理学中这些新信号传导机制的研究具有创新性，可以确定药物作为川崎病有效治疗的潜在候选药物。 公共健康相关性：精神氨酸的病理性积累和精神氨酸诱导的髓鞘形成受损以及少突胶质细胞和髓磷脂的丧失是克拉伯病的“标志”。该提案旨在评估 sPLA2 信号通路抑制剂的功效，以描述疾病机制并确定潜在的疾病机制。 KD 的治疗方法。