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: 10477980
• 负责人: Joseph Alexander Barnes
• 金额: $ 3.52万
• 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/10477980
• 关键词: Address; Adrenoleukodystrophy; Adult; Adverse effects; Aging; Agonist; Animal Model; Atrophic; Attenuated; Binding; Biological Models; Bone Marrow Transplantation; Brain; Cell Culture System; Cells; Central Nervous System; Cerebrum; Child; Cholesterol Homeostasis; Chronic; Clinical; Compensation; Complex; Cuprizone; Defect; Demyelinations; Deterioration; Development; Disease; Disease Progression; Disorder of neurometabolic regulation; Early Diagnosis; Experimental Designs; Fatty Acids; Fatty acid glycerol esters; Fiber; Functional disorder; Gene Targeting; Genes; Genetically Engineered Mouse; Hematopoietic Stem Cell Transplantation; Heterodimerization; Homeostasis; Immune; Immune response; Impairment; Inborn Errors of Metabolism; Individual; Inflammation; Inflammatory; Injury; Innovative Therapy; Intervention; Knowledge; Learning; Lipids; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Microglia; Mitochondria; Modeling; Molecular; Molecular Target; Mutation; Myelin; Neonatal Screening; Nerve Fibers; Nuclear Receptors; Oligodendroglia; Onset of illness; Organelles; Outcome; Oxidative Stress; Pathway interactions; Patients; Penetrance; Peroxisome Proliferator-Activated Receptors; Phenotype; Physicians; Primary Cell Cultures; Process; Prognosis; Protein Isoforms; Reporting; Role; Scientist; Secondary to; Signal Pathway; Spinal Cord; Therapeutic; Tissues; Training; Up-Regulation; Vegetative States; Very Long Chain Fatty Acid; Work; alternative treatment; brain cell; brain tissue; cell type; disability; experience; fatty acid metabolism; fatty acid oxidation; high risk; improved; innovation; insight; lipid metabolism; member; mitochondrial dysfunction; mouse model; multiple datasets; neuroinflammation; novel; novel therapeutics; oxidation; patient subsets; peroxisome; receptor; remyelination; skills; stressor; therapeutic target

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。 ALD的特点是积累很长的链 健康组织中通常含有少量的脂肪酸 (VLCFA)。 VLCFA 的积累 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，导致中枢神经内主要纤维束的恶化 系统（中枢神经系统）。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有 骨髓移植的治疗选择是唯一被批准的 ALD 治疗方法。对于大多数人来说 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 具有接近完全外显率的表型。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 流程。我们发现一个候选靶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- 产生髓磷脂并对髓磷脂维持至关重要的类型。我们观察到基因受以下因素调控 Pparβ/δ 编码 VLCFA 代谢所需的关键成分，上调时可以补偿 用于 ALD 中观察到的 VLCFA 氧化缺陷。在本提案中，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，这将扩大可追求的治疗目标，以及 破译免疫区室的破坏如何加剧疾病进展。为了完成这些 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 接近。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 进展。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。