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: 6900506
• 负责人: KATHELEEN GARDINER
• 金额: $ 7.71万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900506
• 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）：唐氏综合症患者在特定的学习和记忆任务中受损，并表现出早发性认知衰退。在唐氏综合症的Ts65Dn小鼠模型中也描述了类似的缺陷。钙调磷酸酶是一种钙/钙调素依赖性蛋白磷酸酶，介导许多细胞过程，包括突触可塑性。研究者假设钙调磷酸酶信号异常与唐氏综合症和小鼠模型中观察到的认知障碍有关，因为(i)与唐氏综合症和Ts65Dn小鼠中观察到的学习和记忆缺陷相似的钙调磷酸酶信号缺陷可能由钙调磷酸酶信号缺陷引起，（ii） 21号染色体唐氏综合症关键区1 （DSCR1）基因，超氧化物歧化酶（SOD1）， a-淀粉样蛋白前体蛋白（APP），和Purkinjie cell protein 4 （PCP4）均可直接或间接抑制钙调磷酸酶活性。重要的是，在唐氏综合症的大脑中钙调磷酸酶活性降低，初步数据显示Ts65Dn小鼠的大脑中钙调磷酸酶活性也降低。研究者建议，了解唐氏综合症的基因/表型相关性最好通过将实验集中在与认知功能相关的途径上，并预测该途径会被21号染色体基因的过表达所干扰。为了验证该方法对钙调神经磷酸酶通路的作用，她提出了以下具体目标：(1)测量青少年、青年和老年Ts65Dn小鼠脑区钙调神经磷酸酶活性的水平和定位；(2)通过测量钙调神经磷酸酶靶点、内噬蛋白动力学蛋白、凋亡蛋白BAD、淀粉样斑块成分tau、转录因子Elk、NFATc4和CREB以及钙调神经磷酸酶抑制剂DSCR1的磷酸化水平，评估Aim 1中发现的异常的后果；(3)通过在Ts1Cje唐氏综合征小鼠模型中重复Aims 1和2，剖析含有SOD1和APP的基因组区域对钙调神经蛋白相关异常的贡献，该模型仅包含四个候选基因中的DSCR1和PCP4的三体。