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：
8236875
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
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/8236875
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. 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（由应用提供）：Krabbe疾病（KD）是一种发展的神经系统疾病，其特征是由于 - 乳乳糖基核苷酶（GALC）的缺乏，精神病的积累过多和少突胶质细胞（OLS）和髓磷脂的丧失。 KD中OL死亡的机制尚不清楚，因此治疗难以捉摸。这项研究旨在研究心理诱导的OL损失机制，并鉴定阻断OLS作为KD潜在治疗的药物。本提案是基于我们的最初发现，即通过SPLA2信号通路介导了心理诱导的OLS的凋亡损失，并且SPLA2的抑制剂可以防止损失PPAR/过氧化物体功能和OLS的损失。由于酶促活性用于合成心理素是OL分化不可或缺的一部分，因此在分化和OLS分化和丢失中的精神介导机制的描述对于理解KD病理学很重要。基于这些新的发现，我们假设Psychosine的积累与OL分化的特定异常有关，并且SpLA2的激活以及PPAR/ PPAR/过氧化物体功能的抑制参与OL分化及其在KD中的损失的失调。通过药理学抑制剂对这些途径进行基于机理的干预措施在KD中具有治疗潜力。因此，拟议的研究是； 1）研究Psychosine对OLS分化和存活的影响，并阐明了Psychosine介导的OLS分化和生存的失调的机制。 2）评估用于治疗Twitcher（TW）小鼠的SPLA2（DEDA）和抗氧化剂（NAC）抑制剂的治疗效率。这些研究基于我们实验室的最初贡献。观察到的SPLA2在心理体中观察到的作用在培养物以及KD/TW的CNS中诱导的OLS丧失以及SpLA2抑制剂对OLS损失的抑制作用在KD病理学中SplA2介导的信号传导途径的重要性。抑制SPLA2信号通路可以保护OLS免受心理毒性的抑制，这为我们提供了阐明疾病机制并确定KD患者潜在疗法的机会。对KD病理学中这些新型信号传导机制的研究具有创新性，可以将药物视为有效治疗KD的潜在候选者。公共卫生相关性：心理和心理剂引起的髓鞘损害和少突胶质细胞和髓磷脂的丧失是Krabbe病的“标志”。该建议是评估SPLA2信号传导途径抑制剂的有效性，以划定疾病机制，并确定KD的潜在疗法。