Mechanisms of Krabbe Disease Pathobiology and Therapy

描述（由申请人提供）：甲蟹病（KD）是一种发育性神经系统疾病，其特征是由于半乳糖脑苷酶（GALC）缺乏导致精神肽过度积累和少突胶质细胞（OLs）和髓磷脂的损失。KD患者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素诱导的OL损失机制，并确定阻断OL损失的药物作为KD的潜在治疗方法。目前的建议是基于我们最初的发现，即精神素诱导的OLs凋亡损失是通过sPLA2信号通路介导的，sPLA2抑制剂可以防止PPAR/过氧化物酶体功能的丧失和OLs的损失。由于合成精神碱的酶活性的表达是OL分化的组成部分，因此描述精神碱介导的OL分化和损失机制对于理解KD病理非常重要。基于这些新发现，我们假设精神素的积累与OL分化的5期特异性异常有关，sPLA2的激活和PPAR/过氧化物酶体功能的抑制参与了KD中OL分化的失调及其丢失。通过药物抑制剂对这些途径进行基于机制的干预具有治疗KD的潜力。因此，拟进行的研究有；1)探讨精神素对OLs分化和存活的影响，阐明精神素介导的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）治疗抽搐（TW）小鼠的疗效。这些研究是基于我们实验室的原始贡献。我们观察到sPLA2在精神素诱导的培养物和KD/TW中枢神经系统中OLs的丢失以及sPLA2抑制剂对OLs丢失的抑制中所起的作用，证明了sPLA2介导的信号通路在KD病理中的重要性。sPLA2信号通路的抑制保护ol免受精神毒素毒性的影响，这一事实为我们阐明疾病机制和确定KD患者的潜在治疗方法提供了机会。对KD病理中这些新的信号机制的研究具有创新性，并可能确定KD有效治疗的潜在候选药物。

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.