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Role of KCTD proteins in striatal signaling

KCTD 蛋白在纹状体信号传导中的作用

基本信息

批准号：
10734241
负责人：
Brian S Muntean
金额：
$ 38.5万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734241
关键词：
Acute Binding Biochemical Biological Assay Brain CRISPR/Cas technology Caring Cells Clinical Collection Complex Corpus striatum structure Coupled Cyclic AMP Data Deep Brain Stimulation Development Disease Progression Dyskinetic syndrome Dystonia Environment Enzymes Etiology Event Feedback G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Genetic Markers Goals Image Impairment Investigation Knockout Mice Logistics Molecular Motor Movement Disorders Mutation Neurons Optics Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Physiological Physiology Play Positioning Attribute Potassium Channel Prevalence Process Protein Family Proteins Public Health Regulation Research Role Shapes Signal Transduction Signaling Protein Slice Testing Therapeutic Tissues Transducers Variant Work Zinc adenylyl cyclase type V conditional knockout disease-causing mutation insight motor control mouse model nervous system disorder neuroregulation neurotransmission optical sensor postsynaptic pressure receptor sensor targeted treatment therapeutically effective two-photon zinc-binding protein

项目摘要

Project Summary Alterations in striatal cAMP signal transduction contribute to the progression of movement disorders, whose increasing prevalence present a significant public health concern. Therapeutic options for movement disorders are limited in part by a deficient understanding of the molecular control of cAMP signaling in striatal neurons. Although tremendous progress has been made in unraveling the cAMP pathway, complexity of cAMP regulation in the striatum coupled with the large number of players with pivotal roles not yet fully elucidated has slowed progress towards more effective care strategies. To overcome this barrier, our long-term goal is to better understand the mechanisms and principles that control striatal cAMP signaling. The proposed work focuses on the role of Potassium Channel Tetramerization (KCTD) proteins in modulation of striatal signaling through G protein coupled receptors (GPCRs). KCTD proteins were recently implicated in GPCR signaling both directly by engaging with G proteins and indirectly by influencing zinc influx through zinc transporters. However, the details of KCTD regulation of G protein signaling and consequences of zinc on striatal signaling are only beginning to emerge. The goal of this proposal is elucidation of the KCTD-Zinc-cAMP signaling axis in the native neuronal environment. In Aim 1, we will use biochemical assays to study negative feedback pressure that dynamically adjusts KCTD expression in the striatum followed by optical assays to study how KCTD regulate interaction of G proteins with effectors. Aim 2 will utilize biochemical assays and optical sensors in live neurons to delineate precise mechanistic details of KCTD and zinc on striatal cAMP signaling. In Aim 3, we will address how KCTDs shape native physiological signal interrogation by optically stimulating neuromodulatory release with concurrent 2-photon imaging of signal integration across intact circuits in genetically defined striatal neurons expressing optical sensors. In total, the proposed research is expected to be significant in that it will provide essential mechanistic and physiological insight into the KCTD-Zinc-cAMP impact on signaling processes critical for motor physiology.

项目摘要纹状体cAMP信号转导的改变有助于运动障碍的进展，其日益增加的流行率引起了严重的公共卫生问题。运动障碍的治疗选择限制了部分由缺乏了解的纹状体神经元中的cAMP信号的分子控制。尽管在解开cAMP途径方面已经取得了巨大的进展，但cAMP的复杂性仍然是一个未知的问题。纹状体中的调节加上大量的具有关键作用的参与者尚未完全阐明减缓了更有效的护理战略的进展。为了克服这一障碍，我们的长期目标是更好地了解控制纹状体cAMP信号传导的机制和原理。拟议工作着重于钾通道四聚化（KCTD）蛋白在纹状体信号调节中的作用 G蛋白偶联受体（GPCR）。最近发现KCTD蛋白参与GPCR信号转导既直接通过与G蛋白结合，又间接通过影响锌转运蛋白的锌内流。然而，KCTD对G蛋白信号传导的调节以及锌对纹状体信号传导的影响的细节，才刚刚开始出现本提案的目的是阐明KCTD-锌-cAMP信号轴在原生神经元环境。在目标1中，我们将使用生化分析来研究负反馈压力，动态调整KCTD表达在纹状体，其次是光学分析，以研究如何 KCTD调节G蛋白与效应物的相互作用。目标2将利用生化分析和光学传感器活神经元描绘精确的机制细节KCTD和锌对纹状体cAMP信号。在目标3中，我们将讨论KCTD如何通过光学刺激来塑造天然生理信号询问神经调节释放与跨完整回路的信号整合的同时双光子成像，表达光学传感器的遗传定义的纹状体神经元。总的来说，拟议的研究预计将重要的是，它将为KCTD-锌-cAMP提供基本的机制和生理学见解对运动生理学关键信号过程的影响。