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.

项目概要/摘要 肾上腺脑白质营养不良 (ALD) 是一种遗传性代谢紊乱，表现为炎症变性 大脑和进行性脊髓萎缩的特征是非常长的链的积累。 健康组织中通常含有少量的脂肪酸 (VLCFA)。 导致氧化应激损伤、线粒体稳态紊乱等的发生 压力源最终导致脑髓磷脂（绝缘神经纤维的脂肪鞘）和强健的大脑髓磷脂的丧失 神经炎症会导致中枢神经系统内主要纤维束的恶化 尽管通过新生儿筛查进行了早期发现，但只有一小部分患者享受到这一服务。 骨髓移植的治疗选择是大多数 ALD 的唯一批准疗法。 然而，骨髓移植对部分患者无效，特别是对于脊髓萎缩的患者 那么，扩大治疗选择的方法至关重要， 尤其相关的是发现可以帮助逆转疾病的分子靶点和途径 我们发现一个候选目标是被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- 我们观察到，产生髓磷脂并且对于髓磷脂维持至关重要的基因。 Pparβ/δ 编码 VLCFA 代谢所需的关键成分，上调时可以补偿 针对 ALD 中观察到的 VLCFA 氧化缺陷，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 此外，该项目还将揭示 VLCFA 在疾病相关组织中的积累。 ALD 的病理机制的潜在途径，这将扩大可追求的治疗目标，以及 破译免疫区室的破坏如何加剧疾病的进展。 目标是，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 ALD 系统，以及各种成熟的方法和严格设计的实验 总之，这项综合研究将有助于描绘一个可靶向的分子途径。 ALD 的治疗潜力，以及描述与疾病发作和相关的其他分子途径 此外，该项目还将为 PI 提供丰富的培训和学习经验。 促进成为一名熟练且创新的医师科学家。