Disregulation of Calcineurin in Mouse Models of Down Syn

描述(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功能减退。在唐氏综合症的Ts65Dn小鼠模型中也描述了类似的缺陷。钙调神经磷酸酶是一种钙/钙调素依赖的蛋白磷酸酶，参与许多细胞过程，包括突触的可塑性。研究人员假设，钙调神经磷酸酶信号的异常与唐氏综合症和小鼠模型中的认知障碍有关，因为(I)与唐氏综合症患者和Ts65Dn小鼠类似的学习和记忆缺陷可由钙调神经磷酸酶信号缺陷引起，(Ii)染色体21-唐氏综合症关键区域1(DSCR1)基因、超氧化物歧化酶(SOD1)、a-淀粉样前体蛋白(APP)和浦肯杰细胞蛋白4(PCP4)均直接或间接抑制钙调神经磷酸酶的活性。重要的是，唐氏综合症小鼠的大脑中钙调神经磷酸酶活性降低，初步数据显示，Ts65Dn小鼠的大脑中钙调神经磷酸酶活性也降低。这位研究人员建议，了解唐氏综合症的基因/表型相关性最好的方法是将实验集中在与认知功能相关的途径上，并预测会受到21号染色体基因过度表达的干扰。为了验证钙调神经磷酸酶途径的这种方法，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标、内吞蛋白动态蛋白、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因子DSCR1的磷酸化水平，评估目标1中发现的异常的后果；(3)在仅DSCR1和PCP4三体的唐氏综合征Ts1Cje小鼠模型中，通过重复目标1和2来分析含有SOD1和APP的基因组区域对钙调神经磷酸酶相关异常的贡献。 我们建议将这项工作作为RO3来建立她在这一领域的专业知识，描述节段性三体小鼠模型中钙调神经磷酸酶异常的程度，并产生数据来证明对这一途径对认知的贡献的长期、更详细的研究是合理的。这一试点项目的结果将指导未来对潜在遗传机制的研究，以及这一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.