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: 7826953
• 负责人: MARGOT MAYER-PROSCHEL
• 金额: $ 7.66万
• 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 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826953
• 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（由申请人提供）：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影响的中枢神经系统尤其相关，其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病理学的主要目标部位。浦肯野神经元的明显丧失是该疾病的标志，这导致研究主要集中在ATM在该神经元群体中的作用，而对胶质隔室的关注相当少。虽然ATM的功能丧失可能直接影响神经元群体的存活，但越来越明显的是，许多确定的神经系统疾病是由胶质细胞缺陷引起的，特别是在星形胶质细胞隔室中，其然后间接影响周围神经元组分的存活。在试图确定星形胶质细胞是否以及在何种程度上有助于AT中观察到的病理学，我们从纯合ATM缺陷小鼠脑中分离星形胶质细胞，并将其与野生型对照进行比较。从小脑组织（人类病理学的主要部位）分离的星形胶质细胞高度氧化，具有降低的抗氧化反应能力，并以组织和年龄特异性方式显示谷氨酸转运蛋白GLAST的失调。这些功能变化表明，突变的星形胶质细胞群体可能在维持邻近细胞的保护环境的能力方面受到显著损害。谷氨酸转运蛋白GLAST的失调似乎特别重要，因为小脑含有不成比例的多巴胺能神经元，其依赖于由星形胶质细胞控制的适当谷氨酸稳态。有趣的是，突变型星形胶质细胞的损伤不是全局性的，而是区域特异性的，我们的初步结果表明，从相同动物的皮质组织分离的星形胶质细胞在测试参数方面与野生型对照没有差异。这一发现与人类病理学相一致，其中小脑功能受到疾病的最严重和进行性影响。两者合计，我们的观察导致的假设，星形胶质细胞有助于在AT小脑的病理表型。为了验证这一假设，我们将在体内特定的CNS细胞群中诱导AT功能丧失，并确定特定突变细胞类型对小脑神经变性的贡献。目前可用的动物模型不适合进行这项研究，由于过早的细胞死亡和AT功能的整体损失。此外，我们将确定是否有一个关键的脆弱性窗口，在此期间，AT的缺陷导致星形胶质细胞的功能受损。公共卫生相关性：本提案的目的是确定星形胶质细胞在共济失调毛细血管扩张症（AT）中的作用。基于我们的初步研究，我们认为星形胶质细胞在病理学中起着重要作用，并且我们显示了与人类病理学一致的小脑特异性星形胶质细胞功能损伤。为了表征在不存在严重限制现有AT敲除动物寿命的癌症发展的情况下星形胶质细胞隔室中这种损伤的后果，我们提出产生CNS组织特异性诱导型AT突变动物，其发展出与人类患者相似的CNS病理学，并且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。