Genetic Variation in KIBRA and its role in Human Episodic Memory

描述(由申请人提供)：情节记忆包括有意识地根据需要回忆的自传体经历。内侧颞叶的区域，包括海马体，通常被认为是控制情景记忆形成的关键大脑区域，这些区域的退化，例如在阿尔茨海默病期间，往往与记忆丧失有关。尽管记忆在健康和疾病中都扮演着重要的角色，但人们对决定人类记忆表现差异的遗传学知之甚少。为了确定影响记忆的遗传因素，我们对瑞士国籍的个体进行了一项基于记忆表现分层的全基因组关联研究。位于Kibra基因中的SNP rs17070145被发现与记忆能力显著相关，随后在两个独立的队列中得到验证。表达分析表明Kibra转录本在海马区丰富，功能磁共振研究表明，rs17070145T等位基因的非携带者在记忆提取过程中增加了海马区的激活。这些数据表明Kibra在情景记忆的形成中起着至关重要的作用，并导致了一种假设，即Kibra的一个变体存在于记忆表现较差的个体中。这项研究计划的目标是识别这种变异，并确定其对Kibra的影响。这将通过以下方法实现：研究与相关单倍型相关的生物学相关的SNPs；鉴定海马体中表达Kibra的细胞并比较单倍型阴性和阳性个体的差异；通过在体内检测Kibra生物通路的抑制物来影响记忆调节；通过基因转移改变海马区Kibra的表达水平。拟议中的研究将导致对记忆生物学的更全面的了解，希望利用这些信息为那些患有遗忘症的人开发保留记忆的药物。与公共健康相关的以记忆力丧失为症状的疾病是常见的和毁灭性的。目前，我们对记忆的运作过程知之甚少。这项研究计划的目标是扩展一项基因发现，将一种名为Kibra的蛋白质与记忆表现联系起来，以更好地了解它在记忆过程中的作用，希望不仅能加深我们的知识，还能开发新药来保护患有阿尔茨海默氏症等遗忘症的人的记忆功能。

DESCRIPTION (provided by applicant): Episodic memory includes autobiographical experiences that are consciously recalled as desired. Regions of the medial temporal lobe, including the hippocampus, are generally considered to be the key brain regions controlling episodic memory formation, and the degeneration of these regions, such as during Alzheimer's disease, is often associated with memory loss. Despite memory's important role in both health and disease, little is known about the genetics that determine the differences in memory performance in humans. To identify genetic factors influencing memory we performed a whole-genome association study on individuals of Swiss nationality stratified based upon memory performance. SNP rs17070145, located in the gene KIBRA, was found to be significantly associated with memory performance and was subsequently validated in two independent cohorts. Expression analysis indicated that KIBRA transcripts were enriched in the hippocampus, and functional MRI investigation showed that non-carriers of the rs17070145 T allele increased activation of the hippocampus during memory retrieval. These data suggest a crucial role for KIBRA in episodic memory formation and leads to the hypothesis that a variant of KIBRA exists in individuals with lowered memory performance. The goal of this research plan is to identify this variant and determine its impact on KIBRA. This will be achieved by investigating SNPs of biological relevance on the associated haplotype, identifying those cells in the hippocampus that express KIBRA and compare haplotype negative and positive individuals for differences, by examining in vivo inhibitors of the KIBRA biological pathways for memory modulating affects, and by altering the expression levels of KIBRA within the hippocampus through gene transfer. The proposed studies will lead to a more complete understanding of the biology of memory with the hope of leveraging this information to develop memory-sparing pharmaceuticals for those individuals suffering from amnestic disease. PUBLIC HEALTH RELEVANCE Diseases with memory loss as a symptom are common and devastating. We currently understand very little about how the process of memory works. The goal of this research plan is to expand upon a genetic finding linking a protein known as KIBRA to memory performance to better understand its role in the process of memory with the hopes of not only furthering our knowledge but also developing new drugs to preserve memory function in individuals suffering from amnestic diseases like Alzheimer's.