Kalirin Signaling in Spine Morphogenesis and Cognition in Vivo

Kalirin 信号传导在体内脊柱形态发生和认知中的作用

• 批准号: 7677091
• 负责人: MICHAEL Edward CAHILL
• 金额: $ 2.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677091
• 关键词: AMPA Receptors; Actins; Affect; Alzheimer' s Disease; Amyloid; Animals; Area; Behavioral; Binding; Brain; Cerebral cortex; Characteristics; Cognition; Cognitive; Cognitive deficits; DNA Sequence Rearrangement; Data; Dendrites; Dendritic Spines; Development; Down-Regulation; Employee Strikes; Event; Excitatory Synapse; Exhibits; Frequencies; Functional disorder; Genes; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Knock-out; Knockout Mice; Learning; Light; Link; Long-Term Potentiation; Maintenance; Measures; Mediating; Memory; Memory impairment; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neurosciences; Pathogenesis; Pathology; Pathway interactions; Patients; Preparation; Procedures; Prosencephalon; Protein Isoforms; Role; Shapes; Short-Term Memory; Signal Transduction; Signaling Molecule; Site; Slice; Structure; Synapses; Synaptic plasticity; Therapeutic; Up-Regulation; Vertebral column; cognitive function; conditioned fear; density; in vivo; novel; p21 activated kinase; postsynaptic; rho; synaptic function; therapeutic target; transmission process

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.

描述（由申请人提供）：树突棘是大脑中最具兴奋性突触的部位。脊柱密度和形态的变化对于学习和记忆的形成具有重要意义，脊柱功能障碍是阿尔茨海默病（AD）发病机制的早期事件，可能直接导致认知功能障碍。 Rho GEF kalirin 已被证明可以通过激活小 GTPase Rac 来控制树突棘形态发生。 Rac 进而激活 p21 激活激酶 Pak，后者进而介导肌动蛋白细胞骨架重排以及随之而来的脊柱形态变化。最近开发的第一只 Kalirin KO 小鼠将用于确定先前表征的 Kalirin-Rac 和 kalirin-GluR1 体外相互作用是否在 Kalirin KO 动物体内失调。此外，我们将描述 Kalirin KO 动物的认知缺陷，并确定介导这些缺陷的突触信号缺陷。最后，我们将研究 Kalirin 损失如何影响体内突触结构和功能。由于阿尔茨海默病 (AD) 的特点是认知和树突棘缺陷，与 Kalirin 下调引起的缺陷密切相关，而且 Kalirin 缺失是人类阿尔茨海默病患者的一个共同特征，因此了解 Kalirin 在体内的作用具有极大的治疗意义。总体而言，所提出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，由于卡里林损失在阿尔茨海默病患者的前脑中很明显，而且我们提供的初步证据表明卡里林损失是细胞阿尔茨海默病模型的特征，因此卡里林 KO 小鼠的特征可能与其他研究相结合，将卡里林鉴定为一种治疗靶点如 Kalirin 效应分子 Pak 和 GluR1 所示。简单总结：树突棘是大脑中最具兴奋性突触的部位。通过了解树突棘内的信号分子如何影响树突棘密度/形态以及这些分子如何影响学习和记忆等认知功能，可以更好地理解树突棘畸变如何影响认知。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学至关重要。