Disregulation of Calcineurin in Mouse Models of Down Syn

唐氏综合症小鼠模型中钙调神经磷酸酶的失调

• 批准号: 7035930
• 负责人: KATHELEEN GARDINER
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035930
• 关键词: BCL2 gene /protein; Downs syndrome; age difference; amyloid proteins; animal old age; animal tissue; biological signal transduction; calcineurin; disease /disorder model; dynamin; enzyme activity; inhibitor /antagonist; juvenile animal; laboratory mouse; mature animal; phosphorylation; protein localization; superoxide dismutase; tau proteins; transcription factor; western blottings

DESCRIPTION (provided by applicant): Individuals with Down syndrome are impaired in specific learning and memory tasks and display early onset cognitive decline. Similar deficits have been described in the Ts65Dn mouse model of Down syndrome. Calcineurin is a calcium/calmodulin-dependent protein phosphatase that mediates many cellular processes, including synaptic plasticity. The investigator hypothesizes that abnormalities in calcineurin signaling are relevant to the cognitive impairments seen in Down syndrome and mouse models because (i) learning and memory deficits similar to those observed in individuals with Down syndrome and Ts65Dn mice can be caused by calcineurin signaling defects, and (ii) the chromosome 21 Down Syndrome Critical Region 1 (DSCR1) genes, superoxide dismutase (SOD1), a-amyloid precursor protein (APP), and Purkinjie cell protein 4 (PCP4) each directly or indirectly inhibits calcineurin activity. Importantly, calcineurin activity is decreased in Down syndrome brains, and preliminary data show it is also decreased in brains of Ts65Dn mice. The investigator suggests that understanding gene/phenotype correlations in Down syndrome will best be achieved by focusing experiments on a pathway relevant to cognitive function and predicted to be perturbed by overexpression of chromosome 21 genes. To validate this approach for the calcineurin pathway, she proposes the following specific aims: (1) measure levels and localization of calcineurin activity in brain regions of adolescent, young adult, and aged Ts65Dn mice; (2) evaluate the consequences of abnormalities found in Aim 1 by measuring phosphorylation levels of calcineurin targets, endocytic protein dynamin, apoptosis protein BAD, amyloid plaque component tau, transcription factors Elk, NFATc4, and CREB, and calcineurin inhibitor DSCR1; and (3) dissect the contribution to the calcineurin-related abnormalities of the genomic region containing SOD1 and APP by repeating Aims 1 and 2 in the Ts1Cje mouse model of Down syndrome that is trisomic for only DSCR1 and PCP4 of the four candidate genes. We propose this work as an RO3 to establish her expertise in this area, to describe the extent of calcineurin abnormalities in the segmental trisomy mouse models, and to generate data to justify long-term, more detailed investigations of the contribution of this pathway to cognition. Results from this pilot project will direct future studies of the underlying genetic mechanism, as well as behavioral and cognitive consequences of abnormalities in this pathway.

描述（由申请人提供）：患有唐氏综合症的个体在特定的学习和记忆任务中受到损害，并显示早期发作认知能力下降。 唐氏综合症的TS65DN小鼠模型已经描述了类似的缺陷。 钙调蛋白是一种钙/钙调蛋白依赖性蛋白磷酸酶，介导许多细胞过程，包括突触可塑性。 The investigator hypothesizes that abnormalities in calcineurin signaling are relevant to the cognitive impairments seen in Down syndrome and mouse models because (i) learning and memory deficits similar to those observed in individuals with Down syndrome and Ts65Dn mice can be caused by calcineurin signaling defects, and (ii) the chromosome 21 Down Syndrome Critical Region 1 (DSCR1) genes, superoxide dismutase （SOD1），A-淀粉样蛋白前体蛋白（APP）和Purkinjie细胞蛋白4（PCP4）直接或间接抑制钙调神经磷酸酶的活性。 重要的是，唐氏综合症大脑的钙调神经酶活性降低，初步数据表明，TS65DN小鼠的大脑也降低了。 研究者建议，最好通过将实验集中在与认知功能相关的途径上，并预测通过对21个染色体基因过度表达的途径来理解唐氏综合征的基因/表型相关性。 为了验证钙调蛋白途径的这种方法，她提出了以下特定目的：（1）在青少年，年轻成人和年龄较高的TS65DN小鼠的大脑区域中钙调神经素活性的测量水平和定位； （2）通过测量钙调神经蛋白靶标的磷酸化水平，内吞蛋白元激素，凋亡蛋白不良，淀粉样蛋白斑块成分tau，转录因子ELK，NFATC4和CREB和CREBERIN抑制剂DSCR1来评估AIM 1中异常的后果。 （3）通过在唐氏综合征的TS1CJE小鼠模型中重复AIM 1和2，剖析包含SOD1和APP的钙调神经蛋白相关的异常，该模型仅适用于四个候选基因的DSCR1和PCP4。 我们将这项工作作为RO3提出，以在该领域建立她的专业知识，以描述节段三体小鼠模型中钙调神经素异常的程度，并生成数据以证明对这种途径对认知途径的贡献的长期，更详细的研究合理。 该试点项目的结果将指导对潜在遗传机制的未来研究，以及该途径中异常的行为和认知后果。