Ataxia Telangiectasia in the CNS - Cause and Effect

中枢神经系统毛细血管扩张共济失调 - 因果关系

• 批准号: 7599466
• 负责人: MARGOT MAYER-PROSCHEL
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599466
• 关键词: ATM deficient; ATM function; ATM gene; Acute; Address; Affect; Age; Animal Model; Animals; Antioxidants; Astrocytes; Ataxia Telangiectasia; Attention; Brain; Cause of Death; Cell Death; Cells; Cerebellar cortex structure; Cerebellar degeneration; Cerebellum; Chronic; Crossbreeding; Defect; Development; Disease; Disease Progression; Environment; GLAST Protein; Glutamate Transporter; Glutamates; Glutathione; Hereditary Disease; Homeostasis; Human; Human Pathology; Impairment; Knockout Mice; Lead; Longevity; Malignant Neoplasms; Mitotic; Modeling; Mus; Nerve Degeneration; Neurons; Pathology; Pathway interactions; Patients; Phase; Phenotype; Play; Population; Process; Research; Research Personnel; Role; Site; Testing; Time; Tissues; base; cell type; functional loss; gene replacement; in vivo; knockout animal; loss of function; mouse model; mutant; nerve stem cell; nervous system disorder; neuronal survival; novel; preference; premature; prevent; programs; promoter; public health relevance; response

DESCRIPTION (provided by applicant): Ataxia Telangiectasia (AT) is a genetic disorder that surprisingly manifests itself only in certain tissues. This tissue preference is especially relevant to the AT-affected CNS, in which degeneration of the cerebellar cortex and subsequently many of its afferent and efferent neuronal pathways are the major target site for pathology. The obvious loss of Purkinje neurons that is a hallmark of the disease has resulted in studies that mainly focus on the role of ATM in this neuronal population with considerable less attention paid to the glial compartment. While the functional loss of ATM might affect the survival of neuronal populations directly, it is becoming increasingly evident that many defined neurological disorders are caused by glial deficiencies, especially in the astrocyte compartment, which then indirectly affect the survival of surrounding neuronal components. In an attempt to determine whether and to what extend astrocytes contribute to the pathology observed in AT, we isolated astrocytes from homozygous ATM deficient mouse brains and compared them to their wildtype controls. Astrocytes isolated from cerebellar tissue, the major site of human pathology, were highly oxidized, had a decreased ability to mount an anti-oxidant response and showed deregulation of the glutamate transporter GLAST in a tissue and age specific manner. These functional changes suggest that the mutant astrocyte population is likely to be significantly impaired in the ability to maintain a protective environment for neighboring cells. The deregulation of the glutamate transporter GLAST seems particular significant as the cerebellum contains a disproportionate ratio of glutaminergic neurons that rely on proper glutamate homeostasis controlled by astrocytes. Interestingly, the impairment of mutant astrocytes was not global but region specific and our preliminary results show that astrocytes isolated from cortical tissue of the same animals did not differ from wildtype controls in the tested parameters. This finding is consistent with the human pathology in which cerebellar functions are most severely and progressively affected by the disease. Taken together, our observations lead to the hypothesis that astrocytes contribute to the pathological phenotype of the cerebellum in AT. To test this hypothesis we will induce loss of AT function in specific CNS cell populations in vivo and determine the contribution of specific mutant cell types to the neurodegeneration in the cerebellum. Currently available animal models are not suitable to conduct this research due to premature cell death and global loss of AT function. In addition, we will determine whether there is a critical window of vulnerability during which the deficiency in AT leads to impairment of function in astrocytes. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to establish the role of astrocytes in Ataxia Telangiectasia (AT). Based on our preliminary studies we suggest that astrocytes play a major role in the pathology and we show a cerebellar specific impairment of astrocyte function that is consistent with the human pathology. To characterize the consequence of this impairment in the astrocyte compartment in the absence of the cancer development that severely restricts the lifespan of existing AT knockout animals, we propose to generate CNS tissue specific inducible AT mutant animals that develop a CNS pathology similar to the human patients and with a live span that allows us to characterize the role of astrocytes in the disease progression.

描述(申请人提供)：共济失调毛细血管扩张症(AT)是一种遗传性疾病，令人惊讶地只在某些组织中表现出来。这种组织偏好与AT影响的CNS尤其相关，在AT影响的CNS中，小脑皮质的变性以及随后的许多传入和传出神经元通路是主要的病理靶点。作为该病的一个标志，浦肯野神经元的明显丧失导致了研究主要集中在ATM在这一神经元群体中的作用，而对神经胶质室的关注相当少。虽然ATM的功能丧失可能直接影响神经元群体的生存，但越来越明显的是，许多明确的神经疾病是由神经胶质细胞缺陷引起的，特别是星形胶质细胞室，这进而间接影响周围神经元组件的生存。为了确定星形胶质细胞是否以及在多大程度上参与了AT的病理观察，我们从纯合子ATM缺乏的小鼠脑中分离出星形胶质细胞，并将它们与野生型对照进行比较。从人类主要病理部位小脑组织中分离的星形胶质细胞被高度氧化，抗氧化反应能力降低，并以组织和年龄特有的方式表现出谷氨酸转运体GLAST的去调节。这些功能变化表明，突变的星形胶质细胞群体在为邻近细胞维持保护环境的能力方面可能会受到显著损害。谷氨酸转运体GLAST的解除调控似乎特别重要，因为小脑中含有不成比例的谷氨酸能神经元，这些神经元依赖于由星形胶质细胞控制的适当的谷氨酸稳态。有趣的是，突变型星形胶质细胞的损伤不是全局性的，而是区域性的，我们的初步结果表明，从相同动物的皮质组织中分离的星形胶质细胞在测试参数上与野生型对照没有区别。这一发现与人类的病理学相一致，在人类病理学中，小脑功能受到这种疾病的影响最严重和最严重。综上所述，我们的观察结果导致了星形胶质细胞与AT小脑的病理表型有关的假设。为了验证这一假说，我们将在体内诱导特定CNS细胞群中AT功能的丧失，并确定特定突变细胞类型对小脑神经变性的贡献。由于细胞过早死亡和AT功能的全局性丧失，目前可用的动物模型不适合进行这项研究。此外，我们将确定是否存在一个关键的脆弱窗口，在此期间AT缺乏导致星形胶质细胞功能受损。公共卫生相关性：该提案的目的是确定星形胶质细胞在毛细血管扩张性共济失调(AT)中的作用。根据我们的初步研究，我们认为星形胶质细胞在病理中起主要作用，我们显示出与人类病理一致的小脑特异性星形胶质细胞功能损害。在没有严重限制现有AT基因敲除动物寿命的癌症发展的情况下，为了表征这种星形胶质细胞损伤的后果，我们建议产生CNS组织特异性可诱导AT突变动物，该突变动物发展出类似于人类患者的CNS病理，并具有使我们能够表征星形胶质细胞在疾病进展中的作用的寿命。