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：
7390545
负责人：
MARGOT MAYER-PROSCHEL
金额：
$ 19.25万
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 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390545
关键词：
ATM deficient Affect Animals Astrocytes Ataxia Telangiectasia Athetosis Biology Brain Cells Cerebellar degeneration Cerebellum Cerebral cortex Chorea Chromosomes, Human, Pair 7 Class Coculture Techniques Conditioned Culture Media Defect Development Disease Dystonia Environment Exhibits Functional disorder Generations Genetic Genetic Models 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 Numbers Oligodendroglia Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Patients Pattern Perinatal Peripheral Nervous System Diseases Phenotype Physiological Population Process Production Quality of life Range 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潜在的新型细胞靶标，该靶标在遗传疾病性疾病性共济失调（AT）中受到影响。属于一类神经系统疾病，在这些神经系统疾病中，围产期发育似乎正常进展，但最终出现了越来越严重的功能障碍。症状包括对电离辐射的敏感性，眼动作失调，唱片，心脏病，肌张力障碍，周围神经病，不育，染色体7和14的易位，胸腺欠发育不发达的胸腺，并增加了肿瘤的风险。大多数患者在生命的第二个十年或初期死亡，虽然1988年首次确定了负责AT（称为ATM的遗传病变（称为ATM）），但尚未确定已知的疗法。尽管大多数研究集中在主要病理鉴定靶标的生物学上，但小脑神经元的进行性变性，我们的研究揭示了从AT小鼠模型的CNS衍生的星形胶质细胞功能障碍。我们对ATM缺乏的星形胶质细胞的研究表明，在突变体星形胶质细胞中，这些关键功能受损，这些突变体的星形胶质细胞专门存在于小脑（主要病理学的主要部位）中。我们还在共培养实验中表明，缺陷型小脑神经元显示出变性和生长障碍的迹象，而正常的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存活。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原因。该提案扩展了我们的初步观察结果，我们建议在目标1中测试是否在临界功能中损害了来自ATM大脑各个区域的星形胶质细胞，包括控制氧化应激，生长因子的产生和细胞外环境中谷氨酸浓度的调节。在AIM 2中，我们将检验以下假设：星形胶质细胞种群的缺陷已经发生在前体细胞的阶段，引起了星形胶质细胞，因此是细胞内部的，而不是区域性施加的功能障碍。最后，我们扩展了AIM 3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挽救神经元细胞退化的策略。这种纠正将检查三种治疗性相关的可能性：在存在不同比例的正常星形胶质细胞和来自正常星形胶质细胞的条件培养基的情况下，ATM衍生细胞的生长，ATM衍生的Cerebellar星形胶质细胞中AMT异常的遗传校正和氧化应力的遗传校正。该应用程序的组成部分应提供有关星形胶质细胞是否有助于神经元变性的明确信息。如果恢复星形胶质功能是有益的，那么这将为AT的最终治疗提供全新的策略。该提议的重点是我们确定的新细胞靶标的表征，该靶标在遗传疾病性疾病毛道性毛细血管炎（AT）中受到影响，该靶标（AT）属于一类致命神经系统疾病，没有已知的疗法。我们提出的实验将为AT的治疗提供全新的策略。