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）：共济失调的毛细血管扩张（AT）是一种遗传疾病，仅在某些组织中表现出出人意料的表现。这种组织偏好与受感染的CNS特别相关，在该中枢神经系统中，小脑皮层的变性以及随后的许多传入和传染性神经元途径是病理学的主要靶点部位。浦肯野神经元的明显丧失是该疾病的标志，导致研究主要关注ATM在该神经元人群中的作用，对神经胶质腔室的关注较少。虽然ATM的功能丧失可能会直接影响神经元种群的存活，但越来越明显的是，许多定义的神经系统疾病是由神经胶质缺乏引起的，尤其是在星形胶质细胞室中，然后间接影响周围神经元成分的存活。为了确定延伸星形胶质细胞是否有助于AT中观察到的病理的尝试，我们将星形胶质细胞从纯合子ATM缺乏的小鼠大脑中分离出来，并将其与它们的野生型对照进行了比较。从小脑组织中分离出的星形胶质细胞是人类病理的主要部位，被高度氧化，具有降低的抗氧化剂反应的能力，并显示出以组织和年龄为特定方式的谷氨酸转运蛋白胶状的失调。这些功能变化表明，在维持邻近细胞保护环境的能力中，突变体星形胶质细胞种群可能会受到显着损害。谷氨酸转运蛋白的放松管制似乎特别重要，因为小脑包含依赖于由星形胶质细胞控制的适当谷氨酸稳态的谷氨酰胺能神经元的比例不成比例。有趣的是，突变星形胶质细胞的损害不是全局的，而是特定区域的，我们的初步结果表明，从同一动物的皮质组织中分离出的星形胶质细胞与测试参数中的野生型对照没有差异。这一发现与小脑功能最严重和受到疾病逐渐影响的人类病理一致。综上所述，我们的观察结果导致了一个假设，即星形胶质细胞有助于小脑的病理表型。为了检验该假设，我们将在体内诱导特定CNS细胞群体的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，因为过早的细胞死亡和全球功能丧失。此外，我们将确定是否存在脆弱性的临界窗口，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telangictia（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主要作用，并且我们显示了与人类病理一致的小脑特异性损害。在没有严重限制淘汰动物现有的癌症寿命的情况下，在星形胶质细胞室中这种损害的后果表征，我们建议在突变动物上产生CNS组织特异性诱导的cns病理学，从而形成与人类患者相似的CNS病理学，并且使我们的活体系中的角色表征了人类病毒的作用。