Novel Role of Peroxisome Proliferator Activated Receptor Beta/Delta in X-Linked Adrenoleukodystrophy

项目摘要/摘要 肾上腺脑白质营养不良(ALD)是一种遗传性代谢紊乱，表现为炎性变性 大脑和进行性脊髓萎缩。ALD的特征是积累了很长的链 脂肪酸(VLCFA)通常被限制在健康组织中的少量。VLCFA的积聚 导致氧化应激损伤、线粒体动态平衡紊乱等 最终导致脑髓磷脂(隔绝神经纤维的脂肪鞘)丢失的应激源，以及 神经炎症，共同加速中枢神经内主要纤维束的恶化 系统(CNS)。尽管通过新生儿筛查进行早期检测，但只有一小部分患者享受到 骨髓移植的治疗选择，这是ALD唯一被批准的治疗方法。对于大多数人来说 然而，对于患者来说，骨髓移植是无效的，特别是对脊髓萎缩。 具有近乎完全外显的表型。因此，拓宽治疗选择的方法至关重要， 尤其相关的是发现了有助于逆转疾病的分子靶点和途径 流程。我们发现一个候选靶标是被称为过氧化体增殖物激活的核受体。 受体β/德尔塔(PPARβ/δ)，作为脑细胞中各种脂质代谢途径的调节器- 产生髓鞘的类型，对髓鞘的维持至关重要。我们观察到，受 PPARβ/δ编码VLCFA新陈代谢所需的关键成分，当上调时可以补偿 对于在ALD中观察到的VLCFA氧化缺陷。在这个提案中，我们将致力于阐明PPARβ/δ的作用 在ALD的背景下，目的是确定PPARβ/δ可以通过其机制来缓解 VLCFAs在疾病相关组织中的积累。此外，该项目还将揭示新的分子 ALD发病机制的潜在途径，这将放大可追寻的治疗靶点，以及 破译免疫隔间的紊乱如何会加剧疾病的进展。要实现这些目标 旨在，该项目将使用基因工程小鼠和各种原代细胞培养系统作为模型 ALD的系统，以及各种成熟的方法和严格设计的实验 接近了。总而言之，这项全面的研究将有助于描绘一条有针对性的分子途径 ALD的治疗潜力，以及描述与疾病发生和发展相关的其他分子途径 进步。此外，该项目还将为PI提供大量的培训和学习经验 促进培养成为技艺精湛、富有创新精神的内科科学家。

Project Summary/Abstract Adrenoleukodystrophy (ALD) is a hereditary metabolic disorder that manifests with inflammatory degeneration of the brain and progressive spinal cord atrophy. ALD is characterized by an accumulation of very long chain fatty acids (VLCFA) that are usually restricted to small amounts in healthy tissue. The buildup of VLCFAs contributes to the development of oxidative stress injury, disrupted mitochondrial homeostasis, and other stressors that culminate in the loss of brain myelin, the fatty sheath that insulates nerve fibers, and robust neuroinflammation that altogether precipitate the deterioration of the major fiber tracts within the central nervous system (CNS). Despite early detection via newborn screening, only a small fraction of patients enjoys a therapeutic option in bone marrow transplantation, which is the sole approved therapy for ALD. For the majority of patients, however, bone marrow transplantation is ineffective, particularly for the spinal cord atrophy phenotype which has near complete penetrance. Approaches to broaden therapeutic options are critical then, and especially relevant is the discovery of molecular targets and pathways that can help reverse the disease processes. We found that one candidate target is the nuclear receptor called peroxisome proliferator activated receptor beta/delta (Pparβ/δ), which serves as a regulator for various lipid metabolic pathways in the brain cell- type that produces myelin and is critical for myelin maintenance. We have observed that genes regulated by Pparβ/δ encode key components necessary for VLCFA metabolism, which when upregulated can compensate for the VLCFA oxidation defect observed in ALD. In this proposal, we will work to elucidate the role of Pparβ/δ in the context of ALD, with the aims of determining the mechanism by which Pparβ/δ can mitigate the accumulation of VLCFAs in disease relevant tissues. Additionally, this project will reveal novel molecular pathways underlying the pathomechanism of ALD, which will amplify pursuable therapeutic targets, as well as decipher how disruptions in the immune compartment can aggravate disease progression. To accomplish these aims, the project will employ genetically engineered mice and various primary cell culture systems as model systems for ALD, along with an assortment of well-established methods and rigorously designed experimental approaches. In sum, this comprehensive study will help delineate a targetable molecular pathway with therapeutic potential for ALD, as well as describe additional molecular pathways pertinent to disease onset and progression. Additionally, this project will also provide the PI with a substantial training and learning experience to facilitate the development into a skilled and innovative physician scientist.