Disregulation of Calcineurin in Mouse Models of Down Syn

描述（由申请人提供）：唐氏综合征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下降。 在唐氏综合征的Ts 65 Dn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。 研究者假设钙调神经磷酸酶信号传导的异常与唐氏综合征和小鼠模型中观察到的认知障碍相关，因为（i）与唐氏综合征个体和Ts 65 Dn小鼠中观察到的那些相似的学习和记忆缺陷可以由钙调神经磷酸酶信号传导缺陷引起，以及（ii）染色体21唐氏综合征关键区域1（DSCR 1）基因、超氧化物歧化酶（SOD 1）、α-淀粉样前体蛋白（APP）和浦肯杰细胞蛋白4（PCP 4）各自直接或间接抑制钙调磷酸酶活性。 重要的是，唐氏综合征大脑中的钙调神经磷酸酶活性降低，初步数据显示它在Ts 65 Dn小鼠的大脑中也降低。 研究人员建议，了解唐氏综合征的基因/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来实现，并预测会受到21号染色体基因过表达的干扰。 为了验证钙调磷酸酶通路的这种方法，她提出了以下具体目标：（1）测量青少年，年轻成年和老年Ts 65 Dn小鼠脑区域中钙调磷酸酶活性的水平和定位;（2）通过测量钙调磷酸酶靶、内吞蛋白动力蛋白、凋亡蛋白BAD、淀粉样斑块组分tau的磷酸化水平，转录因子Elk、NFATc 4和CREB，以及钙调磷酸酶抑制剂DSCR 1;和（3）通过在唐氏综合征的Ts 1Cje小鼠模型中重复目的1和2，剖析对含有SOD 1和APP的基因组区域的钙调磷酸酶相关异常的贡献，所述唐氏综合征小鼠模型对于四个候选基因中的仅DSCR 1和PCP 4是三体的。 我们建议这项工作作为RO 3建立她在这一领域的专业知识，描述在节段性三体小鼠模型中钙调神经磷酸酶异常的程度，并生成数据，以证明长期的，更详细的调查，这条途径对认知的贡献。 该试点项目的结果将指导未来对潜在遗传机制的研究，以及该途径异常的行为和认知后果。

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.