Mechanisms of Krabbe Disease Pathobiology and Therapy

描述(申请人提供)：Krabbe病(KD)是一种发育性神经疾病，其特征是由于缺乏β-半乳糖基脑苷酶(GALC)，精神糖过度聚集，少突胶质细胞(OL)和髓鞘丢失。KD的OL死亡机制尚不清楚，因此治疗一直难以捉摸。本研究旨在探讨精神诱导性OL丢失的机制，并寻找阻断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，即精神病素诱导的OL的凋亡丢失是通过sPLA2信号通路介导的，sPLA2的抑制剂可以防止PPAR/过氧化体功能的丧失和OL的丢失。由于精神肽合成的酶活性的表达是OL分化所必需的，所以阐明精神肽在OL分化和缺失中的介导机制对于理解KD的病理非常重要。基于这些新的发现，我们假设精神药物的积聚与(S)期别的OL分化异常有关，sPLA2的激活和PPAR/过氧化体功能的抑制参与了KD的OL分化的失调和它们的丧失。通过药物抑制剂对这些通路进行基于机制的干预，具有治疗KD的潜力。因此，本研究拟从以下几个方面进行：1)探讨精神病素对OL分化和存活的影响，并阐明精神病素对OL分化和存活的调控机制。2)评价sPLA2抑制剂(DEDA)和抗氧化剂(NAC)对Twitcher(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。SPLA2在神经素诱导的原代培养和KD/TW中枢神经系统中的OLS丢失中的作用以及sPLA2抑制剂对OLS丢失的抑制作用证明了sPLA2介导的信号通路在KD发病机制中的意义。事实上，抑制sPLA2信号通路可以保护OL免受精神药物的毒性，这为我们阐明KD的发病机制和寻找潜在的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是创新的，可能确定药物(S)为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.