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Glial Dysfunction in Ataxia Telangiectasia

共济失调毛细血管扩张症中的神经胶质功能障碍

基本信息

批准号：
7589802
负责人：
MARGOT MAYER-PROSCHEL
金额：
$ 23.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589802
关键词：
ATM deficient Affect Animals Astrocytes Ataxia Telangiectasia Athetosis Biology Brain Cells Cerebellar degeneration Cerebellum Cerebral cortex Chorea Chromosomes, Human, Pair 7 Coculture Techniques Conditioned Culture Media Defect Development Disease Dystonia Environment Exhibits Functional disorder Generations Genetic Glutamates Glutathione Growth Growth Factor Hereditary Disease Homeostasis Impairment In Vitro Infertility Ionizing radiation Lesion Life Mitogens Mus Mutation Nature Neoplasms Nerve Degeneration Neuroglia Neurons Oligodendroglia Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Patients Pattern Perinatal Peripheral Nervous System Diseases Phenotype Physiological Population Process Production Quality of life Regulation Risk Role Site Source Spinal Cord Spinal Cord Diseases Staging Stem cells Stress Symptoms Synaptic plasticity Testing Thymus Gland Time Tissues ataxia telangiectasia mutated protein cellular targeting extracellular in vivo mouse model mutant nervous system disorder novel oculomotor precursor cell regional difference research study restoration spinal cord repair synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): This proposal is focused on defining and characterizing a potentially novel cellular target that is affected in the genetic disease Ataxia telangiectasia (AT). AT belongs to a class of neurological disorders in which perinatal development can appear to progress normally, but in which increasingly severe dysfunction eventually emerges. Symptoms include sensitivity to ionizing radiation, oculomotor apraxia, chorea, athetosis, dystonia, peripheral neuropathy, infertility, translocations of chromosomes 7 and 14, underdeveloped thymus, and increased risk of neoplasms leading to poor quality of life. Most patients die during the second or early third decade of life and while the genetic lesions responsible for AT (called ATM, for AT-mutated) were first identified in 1988, no known therapy has been identified. While the majority of studies are focused on the biology of the primary pathological identifiable target, the progressive degeneration of cerebellar neurons, our studies revealed dysfunction in astrocytes derived from the CNS of a mouse model of AT. Our studies on ATM deficient astrocytes show that a number of critical functions are impaired in mutant astrocytes that specifically reside in the cerebellum, the major site of pathology. We also show in co-cultures experiments that AT-deficient cerebellar neurons shows signs of degeneration and growth impairment, while normal wildtype astrocytes seem to be able to maintain the integrity of mutant neurons and support their survival. These result suggest that the astrocytic dysfunction in AT might be a significant contributor to the neuronal pathology. This proposal extends upon our preliminary observations and we propose to test in Aim 1 whether and to what degree astrocytes derived from various regions of ATM brains are compromised in critical functions, including control of oxidative stress, production of growth factors and regulation of glutamate concentrations in the extracellular environment. In Aim 2 we will test the hypothesis that the defect in the astrocyte population is already occurring on the stage of the precursor cells that give rise to astrocytes and is hence a cell-intrinsic rather than regionally imposed dysfunction. Finally, we extend in Aim 3 our co-culture experiments to determine strategies that can be used to correct astrocyte function and rescue neuronal cells from degeneration. Such correction will examine three therapeutically relevant possibilities: growth of ATM-derived cells in the presence of varying proportions of normal astrocytes and of conditioned medium derived from normal astrocytes, genetic correction of abnormalities in ATM-derived cerebellar astrocytes and pharmacological manipulation of astrocytes to reduce their oxidative stress. The components of this application should provide clear information on whether astrocytes contribute to the neuronal degeneration. If restoration of astrocytic function proves beneficial, this would provide an entirely new strategy to the eventual treatment of AT. This proposal is focused on the characterization of a novel cellular target we have identified that is affected in the genetic disease Ataxia telangiectasia (AT), which belongs to a class of fatal neurological disorders with no known therapy. We propose experiments that would provide an entirely new strategy to the treatment of AT.

描述（由申请人提供）：该提案的重点是定义和表征受遗传病毛细血管扩张共济失调（AT）影响的潜在新细胞靶点。 AT 属于一类神经系统疾病，围产期发育看似正常，但最终会出现越来越严重的功能障碍。症状包括对电离辐射敏感、动眼神经失用、舞蹈症、手足徐动症、肌张力障碍、周围神经病变、不孕、7号和14号染色体易位、胸腺发育不全以及导致生活质量差的肿瘤风险增加。大多数患者在生命的第二个或第三个十年初期死亡，虽然导致 AT 的基因病变（称为 ATM，AT 突变）于 1988 年首次被发现，但尚未确定任何已知的治疗方法。虽然大多数研究都集中在主要病理可识别目标的生物学上，即小脑神经元的进行性变性，但我们的研究揭示了来自 AT 小鼠模型中枢神经系统的星形胶质细胞功能障碍。我们对 ATM 缺陷星形胶质细胞的研究表明，突变星形胶质细胞的许多关键功能受到损害，这些星形胶质细胞专门存在于小脑（病理的主要部位）中。我们还在共培养实验中表明，AT 缺陷的小脑神经元表现出退化和生长障碍的迹象，而正常野生型星形胶质细胞似乎能够维持突变神经元的完整性并支持其生存。这些结果表明 AT 中的星形细胞功能障碍可能是神经元病理学的重要贡献者。该提议扩展了我们的初步观察结果，我们建议在目标 1 中测试来自 ATM 大脑各个区域的星形胶质细胞的关键功能是否以及在多大程度上受到损害，包括氧化应激的控制、生长因子的产生以及细胞外环境中谷氨酸浓度的调节。在目标 2 中，我们将检验以下假设：星形胶质细胞群体的缺陷已经发生在产生星形胶质细胞的前体细胞阶段，因此是细胞固有的而不是区域性强加的功能障碍。最后，我们在目标 3 中扩展了我们的共培养实验，以确定可用于纠正星形胶质细胞功能并拯救神经元细胞免于退化的策略。这种校正将检查三种与治疗相关的可能性：ATM衍生细胞在不同比例的正常星形胶质细胞和正常星形胶质细胞衍生的条件培养基存在下的生长，ATM衍生小脑星形胶质细胞异常的遗传校正以及星形胶质细胞的药理操作以减少其氧化应激。该应用程序的组件应提供关于星形胶质细胞是否导致神经元变性的明确信息。如果星形胶质细胞功能的恢复被证明是有益的，这将为 AT 的最终治疗提供一种全新的策略。该提案的重点是我们已确定的新细胞靶标的特征，该靶标受到遗传病共济失调毛细血管扩张症（AT）的影响，这种疾病属于一类致命的神经系统疾病，目前尚无已知的治疗方法。我们提出的实验将为 AT 的治疗提供全新的策略。