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.

项目摘要/摘要 肾上腺素肌营养不良（ALD）是一种遗传代谢疾病，表现为炎症性变性 大脑和进行性脊髓萎缩。 ALD的特征是累积很长的链 脂肪酸（VLCFA）通常仅限于健康组织中的少量。 VLCFA的积累 有助于氧化应激损伤的发展，线粒体稳态中断和其他 最终导致大脑髓磷脂的压力，隔离神经纤维的脂肪鞘和健壮的脂肪鞘 神经炎症完全是珍贵的中枢神经内主要纤维区域的定义 系统（CNS）。尽管通过新生儿筛查提早发现，但只有一小部分患者享受 骨髓移植中的治疗选择，这是ALD的唯一批准疗法。大多数 然而，在患者中，骨髓移植无效，特别是对于脊髓萎缩 表型几乎完全渗透。那么，扩展热选择的方法至关重要， 发现分子靶标和途径的发现尤其相关，可以帮助扭转疾病 过程。我们发现，一个候选目标是被激活的核接收器称为过氧化物组增殖物 受体β/Delta（PPARβ/δ），它是脑细胞中各种脂质代谢途径的调节剂 产生髓磷脂的类型对于髓磷脂维持至关重要。我们已经观察到受到调节的基因 PPARβ/δ编码VLCFA代谢所需的关键成分 对于在ALD中观察到的VLCFA氧化缺陷。在此提案中，我们将努力阐明PPARβ/δ的作用 在ALD的背景下，以确定PPARβ/δ可以减轻的机制 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的病理机理的基础，该途径将扩大可追求的治疗靶标的以及 解释免疫区室中的破坏如何加剧疾病进展。完成这些 目的，该项目将采用基因工程的小鼠和各种主要细胞培养系统作为模型 ALD的系统，以及各种各样的公认方法和严格设计的实验 方法。总而言之，这项全面研究将有助于描绘有目标的分子途径 ALD的治疗潜力，并描述与疾病发作和 进展。此外，该项目还将为PI提供大量的培训和学习经验 促进发展成为熟练和创新的物理科学家。