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）是一种遗传性代谢疾病，表现出炎症性变性 大脑和程序性脊髓萎缩的特征是很长的链 脂肪酸（vlcfa）通常限于小型肌肉组织。 有助于氧化应激损伤的发展，米孔氏症稳态破坏和其他 最终导致脑髓磷脂的压力，隔离神经纤维的脂肪鞘和健壮的脂肪鞘 神经炎症完全沉淀出中枢神经内的主要纤维。 系统（CNS）。 骨髓移植中的治疗选择，这是ALD的唯一批准疗法。 然而，在患者中，骨髓透明度无效，特别是对于脊髓萎缩 当时，具有几乎完整的外观的表型至关重要。 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。 受体β/delta（PPARβ/δ），在脑细胞中的脂质代谢途径相反 产生髓磷脂的类型，对髓鞘维持至关重要。 PPARβ/δ编码VLCFA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，我们会阐明PPARβ/δ的作用 在ALD的背景下，目的是确定PPARβ/δ可以减轻您的机制 VLCFA在疾病相关组织中的积累。 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的进展。 目的，该项目将以基因发动机的小鼠和各种主要的培养系统作为模型来发挥作用 ALD的系统，以及各种各样的完善方法和严格的设计实验 求助。 ALD的治疗潜力，以及与疾病发作有关的描述性分子途径 进度。 为了促进发展成为熟练和创新的医师科学家。