Kalirin Signaling in Spine Morphogenesis and Cognition in Vivo

描述(申请人提供)：树突棘是大脑中大多数兴奋性突触的位置。脊柱密度和形态的改变对学习和记忆的形成具有重要意义，而脊柱功能障碍是阿尔茨海默病(AD)发病机制中的早期事件，可能直接导致认知功能障碍。研究表明，Rho Global Kalirin通过激活小的GTP酶Rac来控制树突状棘突的形态发生。Rac进而激活p21激活的蛋白激酶Pak，进而介导肌动蛋白细胞骨架重排，从而导致脊柱形态的改变。最近开发的第一只Kalirin KO小鼠将被用来确定先前描述的Kalirin-RAC和Kalirin-GluR1在体外的相互作用在Kalirin KO动物体内是否存在失调。此外，我们将描述加里林KO动物的认知缺陷，并确定调节这些缺陷的突触信号缺陷。最后，我们将研究Kalirin缺失对体内突触结构和功能的影响。由于阿尔茨海默病(AD)的特点是认知和树突棘突缺陷，与Kalirin下调导致的缺陷非常相似，而且Kalirin丢失是人类阿尔茨海默病患者的共同特征，因此了解Kalirin在体内的作用具有极端的治疗意义。总体而言，拟议的目标将对理解树突棘功能障碍如何影响体内记忆学习产生巨大影响，这是神经科学的一个领域，人们猜测很多，但知之甚少。此外，由于Kalirin丢失在阿尔茨海默病患者的前脑中很明显，而且我们提出的初步证据表明Kalirin丢失是细胞阿尔茨海默病模型的特征，因此Kalirin KO小鼠的特征结合其他研究可能确定Kalirin作为治疗靶点，正如Kalirin效应器分子Pak和GluR1所建议的那样。总结：树突棘是大脑中大多数兴奋性突触的位置。通过了解树突棘内的信号分子如何影响脊椎密度/形态，以及这些分子如何影响学习和记忆等认知功能，将更好地理解脊柱异常如何影响认知。此外，了解突触功能障碍对认知的影响对于更全面地了解阿尔茨海默病的病理机制至关重要。

DESCRIPTION (provided by applicant): Dendritic spines are the sites of most excitatory synapses in the brain. Changes in spine density and morphology are of significance for the formation of learning and memory, and spine dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that likely directly contributes to cognitive dysfunctions. The Rho GEF kalirin has been shown to control dendritic spine morphogenesis via its activation of the small GTPase Rac. Rac in turn activates the p21-activated kinase, Pak, which in turn mediates actin cytoskeletal rearrangement and consequent changes in spine morphology. The recent development of the first kalirin KO mouse will be used to determine if the previously characterized kalirin- Rac and kalirin-GluR1 in vitro interactions are dysregulated in kalirin KO animals in vivo. Furthermore we will characterize the cognitive deficits of kalirin KO animals and determine the synaptic signaling deficits that mediate these deficits. Last, we will examine how kalirin loss affects synaptic structure and function in vivo. Because Alzheimer's disease (AD) is characterized by cognitive and dendritic spine deficits that closely parallel those induced by kalirin down-regulation, and because kalirin loss is a common feature of human Alzheimer's patients, understanding the role of kalirin in vivo is of extreme therapeutic relevance. Overall, the proposed aims will have enormous implications for understanding how dendritic spine dysfunctions affect learning a memory in vivo, an area of neuroscience is much is speculated, but little is known. In addition, because kalirin loss is evident in the forebrain of Alzheimer's patients, and because we present preliminary evidence indicating that kalirin loss is characteristic of a cellular Alzheimer's model, the characterization of the kalirin KO mouse may in conjunction with addition studies identify kalirin as a therapeutic target as has been suggested for the kalirin effector molecules Pak and GluR1. Lay Summary: Dendritic spines are sites of most excitatory synapses in the brain. By understanding how signaling molecules within dendritic spines affect spine density/morphology and how these molecules affect cognitive functions such as learning and memory, a better understanding how spine aberrations affect cognition will be determined. In addition, an understanding of the effects of synaptic dysfunction on cognition is of fundamental importance to more completely understanding the pathology of Alzheimer's disease.