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

过氧化物酶体增殖物激活受体β/δ在X连锁肾上腺脑白质营养不良中的新作用

• 批准号: 10312533
• 负责人: Joseph Alexander Barnes
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312533
• 关键词: Novel; Role; Peroxisome; Proliferator; Activated

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.

项目总结/摘要 肾上腺脑白质营养不良（ALD）是一种以炎症性变性为主要表现的遗传性代谢紊乱 以及进行性脊髓萎缩ALD的特征在于非常长的链的积累， 脂肪酸（VLCFA）通常仅限于健康组织中的少量。VLCFA的建立 有助于氧化应激损伤、线粒体稳态破坏等的发展 压力源，最终导致脑髓鞘的损失，绝缘神经纤维的脂肪鞘， 神经炎症，共同加速中枢神经系统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有 骨髓移植是ALD的唯一获批治疗方法。为广大 然而，骨髓移植对脊髓萎缩的患者无效，尤其是对脊髓萎缩的患者。 表型几乎完全突变。因此，扩大治疗选择的方法至关重要， 尤其重要的是发现了有助于逆转这种疾病的分子靶点和途径 流程.我们发现一个候选靶点是称为过氧化物酶体增殖物激活的核受体 受体β/δ（Pparβ/δ），作为脑细胞中各种脂质代谢途径的调节剂， 产生髓磷脂并对髓磷脂的维持至关重要的类型。我们已经观察到， Pparβ/δ编码VLCFA代谢所需的关键成分，当上调时可以进行补偿 对于ALD中观察到的VLCFA氧化缺陷。在这个建议中，我们将努力阐明Pparβ/δ的作用， 在ALD的背景下，目的是确定Pparβ/δ可以减轻 VLCFA在疾病相关组织中的积累。此外，该项目将揭示新的分子 ALD病理机制的潜在途径，这将扩大可追踪的治疗靶点，以及 破解免疫区室的破坏如何加剧疾病进展。完成这些 该项目将采用基因工程小鼠和各种原代细胞培养系统作为模型， 系统的ALD，沿着与各种完善的方法和严格设计的实验 接近。总之，这项全面的研究将有助于描绘一个有针对性的分子途径， ALD的治疗潜力，以及描述与疾病发作相关的其他分子途径， 进展此外，该项目还将为PI提供大量的培训和学习经验 以促进发展成为一个熟练和创新的医生科学家。