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

• 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
• 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

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)：这项提案的重点是定义和表征在遗传性疾病毛细血管扩张性共济失调(AT)中受到影响的潜在的新细胞靶点。AT属于神经系统疾病的一类，在这种疾病中，围产期发育可以看起来正常进行，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，动眼失用，舞蹈症，手足徐动症，肌张力障碍，周围神经病变，不孕不育，7号和14号染色体易位，胸腺发育不全，肿瘤风险增加，导致生活质量下降。大多数患者在生命的第二个十年或第三个十年早期死亡，虽然导致AT的遗传损伤(称为ATM，即AT突变)在1988年首次被发现，但目前还没有已知的治疗方法。虽然大多数研究集中在主要病理可识别靶点的生物学上，即小脑神经元的进行性退化，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，突变型星形胶质细胞的一些关键功能受到损害，这些突变星形胶质细胞特定地驻留在小脑，即主要的病理部位。我们还在共培养实验中发现，AT缺乏的小脑神经元显示出退化和生长障碍的迹象，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，并支持它们的生存。这些结果提示AT的星形胶质细胞功能障碍可能是导致神经元病理改变的重要因素。这一建议扩展了我们的初步观察，我们建议在目标1中测试来自ATM大脑不同区域的星形胶质细胞是否以及在多大程度上受到关键功能的损害，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。在目标2中，我们将检验这一假设，即星形胶质细胞群体中的缺陷已经发生在形成星形胶质细胞的前体细胞的阶段，因此是细胞固有的而不是区域强加的功能障碍。最后，在目标3中，我们扩展了我们的共培养实验，以确定可以用于纠正星形胶质细胞功能和拯救神经细胞免于退化的策略。这种纠正将考察三种与治疗相关的可能性：ATM来源的细胞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液中的生长，对ATM来源的小脑星形胶质细胞异常的遗传纠正，以及对星形胶质细胞的药物操纵以减少其氧化应激。这个应用程序的组件应该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的最终治疗提供一个全新的策略。这项提议的重点是描述我们已经确定的一个新的细胞靶点，该靶点在遗传性疾病毛细血管扩张性共济失调(AT)中受到影响，AT属于一类致命的神经疾病，目前还没有已知的治疗方法。我们提出的实验将为AT的治疗提供一种全新的策略。