Contributions of Iron Regulatory Proteins and Ferroptosis to Neurodegeneration

铁调节蛋白和铁死亡对神经退行性变的贡献

• 批准号: 10430755
• 负责人: McKale Montgomery
• 金额: $ 29.27万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430755
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Antidiabetic Drugs; Apoptosis; Binding; Binding Proteins; Biogenesis; Biological Process; Brain; Brain Diseases; Cell Death; Cells; Clinical; Data; Dementia; Dependence; Development; Disease; Disease Progression; Elements; Free Radicals; Frontotemporal Dementia; Genes; Genetic Translation; Goals; Health; Homeostasis; Human; Incidence; Iron; Iron-Regulatory Proteins; Lead; Link; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Oxidation-Reduction; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pharmacology; Pioglitazone; Predisposition; Prevention; Proteins; Regulation; Research; Rodent; Role; Sulfur; System; TFRC gene; Tauopathies; Testing; Therapeutic; Transgenic Organisms; Work; Zebrafish; age related; age related neurodegeneration; cell injury; dementia risk; erastin; experimental study; healthy aging; improved; inhibitor; iron metabolism; metal transporting protein 1; mutant; neuroblast; normal aging; overexpression; preservation; protein expression; restoration; senescence; targeted treatment; tau Proteins; tau mutation; uptake

1 Project Summary 2 Levels of redox active iron accumulate during both normal aging and neurodegenerative disease progression. Thus, 3 strategies for mitigating iron-mediated cellular damage could be used to promote healthy aging and protect against 4 neurodegenerative decline. One such approach may be through the prevention of ferroptosis, a form of iron-mediated 5 programmed cell death. However, we must first understand how cells manipulate the homeostatic regulators of iron 6 metabolism to contribute to disease before we can fully develop iron-targeted therapeutic strategies. The iron regulatory 7 proteins 1 and 2 (IRP1 and IRP2) are the master regulators of intracellular iron homeostasis because they coordinate the 8 expression of proteins involved in iron storage, uptake, and efflux. Yet, the roles and regulation of IRPs during cellular 9 ferroptosis remain unknown. The long-term goal of the Montgomery lab is to understand how acquisition of exaggerated 10 amounts of iron promote metabolic perturbations that lead to iron-mediated disease progression. The primary objective 11 of this work is to establish how IRP mRNA binding activity influences cellular sensitivity to ferroptotic cell death. The 12 central hypothesis is that increased IRP mRNA binding activity promotes cellular iron accumulation and facilitates 13 ferroptotic cell death. To test this hypothesis, in Aim 1, we will utilize primary neurons isolated from zebrafish injected 14 with IRP1 and IRP2 morpholinos to assess IRP-dependent differences in susceptibility to ferroptotic cell death. 15 Intriguingly, pathologically modified tau can also inhibit iron efflux, and the resulting iron accumulation has been 16 associated with neuronal ferroptosis and dementia progression, but the role of IRPs in ferroptosis and tau-mediated 17 neurodegeneration remains undefined. Thus, in Aim 2, we will utilize a zebrafish model of tauopathy determine the extent 18 to which ferroptosis inhibition protects against neurodegeneration in and IRP-dependent manner. Such studies are 19 important because uncontrolled activation of ferroptosis can further exacerbate neurodegeneration in tau-mediated 20 pathologies such as Alzheimer’s disease and related dementias (ADRD). Thus, findings from this work could lead to 21 improved therapeutic strategies for mitigating iron associated ADRD risks and improving ADRD patient outcomes.

1项目概要 2氧化还原活性铁的水平在正常衰老和神经退行性疾病进展期间积累。因此，在本发明中， 减轻铁介导的细胞损伤的3种策略可用于促进健康衰老和预防 4神经退行性衰退。一种这样的方法可能是通过预防铁凋亡，一种铁介导的 5细胞程序性死亡然而，我们必须首先了解细胞如何操纵铁的稳态调节器 6代谢有助于疾病之前，我们可以充分制定铁靶向治疗策略。铁规 7蛋白1和2（IRP1和IRP2）是细胞内铁稳态的主要调节因子，因为它们协调细胞内铁的代谢。 图8涉及铁储存、吸收和流出的蛋白质的表达。然而，IRP在细胞内的作用和调节 9铁下垂症仍未知。蒙哥马利实验室的长期目标是了解夸大的 铁的量促进导致铁介导的疾病进展的代谢紊乱。主要目的 这项工作的目的是确定IRP mRNA结合活性如何影响细胞对铁凋亡细胞死亡的敏感性。的 12中心假设是IRP mRNA结合活性增加促进细胞铁积累，并促进细胞铁积累。 13例铁凋亡细胞死亡。为了验证这一假设，在目标1中，我们将利用从注射了神经毒素的斑马鱼中分离的原代神经元， 14与IRP1和IRP2吗啉代，以评估IRP依赖性差异的铁凋亡细胞死亡的易感性。 15有趣的是，病理修饰的tau蛋白也可以抑制铁的流出，并且由此产生的铁积累已经被研究。 16与神经元铁凋亡和痴呆进展相关，但IRP在铁凋亡和tau介导的 17神经退行性变仍不明确。因此，在目标2中，我们将利用tau蛋白病的斑马鱼模型来确定 18，其中铁凋亡抑制以IRP依赖性方式保护神经变性。此类研究 19重要，因为铁凋亡的不受控制的激活可以进一步加剧tau介导的神经变性。 20病理学，如阿尔茨海默病和相关痴呆症（ADRD）。因此，这项工作的结果可能导致 21种改善的治疗策略，用于减轻铁相关ADRD风险并改善ADRD患者结局。