Cilia-specific cAMP plays a major role in aneurysm

纤毛特异性 cAMP 在动脉瘤中起重要作用

基本信息

批准号：
10214677
负责人：
Surya Nauli
金额：
$ 34.5万
依托单位：
CHAPMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214677
关键词：
Adult Aneurysm Blood Vessels Cell Compartmentation Cell physiology Cells Chromosomal translocation Cilia Cilostazol Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoplasm Cytosol Data Databases Development Disease Drug Delivery Systems Drug Screening Embryo Endothelial Cells Ensure Forskolin Genes Genetic Genomic Instability Image Knock-out Knockout Mice Laboratories Link Modeling Molecular Mus Mutation Nanotechnology Organelles Pathway interactions Patients Pharmacology Phenotype Physiological Play Polyploidy Protein Kinase Proteins Publications Reagent Reporter Role Sensory Signal Pathway Signal Transduction Single Nucleotide Polymorphism Spectral Karyotyping Stimulus Techniques Testing United States National Institutes of Health Vascular Endothelium Work apical membrane cellular imaging ciliopathy functional improvement genetic approach imaging system improved in vivo inhibitor/antagonist knock-down knowledge base malformation mouse model nanoparticle nanoparticle drug novel novel strategies phosphoric diester hydrolase prevent public health relevance response sensor small hairpin RNA spatiotemporal therapeutic target tool

项目摘要

PROJECT DESCRIPTION Cyclic adenosine monophosphate (cAMP) signaling regulates diverse pathways and cellular functions that result in specific responses when compartmentalized. However, the role of cAMP in cilia function is poorly understood, despite the implication of cAMP in the development of ciliopathies. Using two novel techniques, nanoparticle drug delivery and a single-cell imaging system, our preliminary data indicate that changes in cAMP within a cilium could be independent from those in the cytosol. Furthermore, we have preliminary evidence that inhibition of phosphodiesterase-3 (PDE3), an inactivator of cAMP, can restore ciliary function in ciliopathy models that are prone to aneurysm, and that aneurysmal vessels are characterized by genomic instability. Here, we hypothesize that ciliary cAMP plays an important role in aneurysm formation, and we propose to test if PDE3 is involved in vascular aneurysm via genomic instability (Aim 1) and clarify its role in cAMP signaling in primary cilia (Aim 2). Overall, we will test the idea if a single cilium could be a critical sensor acting as a responsive PDE/cAMP compartment.

项目描述环状腺苷单磷酸（CAMP）信号传导调节导致的多种途径和细胞功能在分隔时的特定响应中。但是，营地在纤毛功能中的作用知之甚少，尽管cAMP在纤毛病的发展中含义。使用两种新技术，纳米颗粒药物输送和单细胞成像系统，我们纤毛可以独立于细胞质中的纤维。此外，我们有抑制作用的初步证据磷酸二酯酶3（PDE3）是一种cAMP的灭活剂，可以恢复纤毛病模型中的纤毛功能容易发生动脉瘤，动脉瘤血管的特征是基因组不稳定性。在这里，我们假设该睫状营在动脉瘤形成中起着重要作用，我们建议测试PDE3是否参与通过基因组不稳定性（AIM 1）进行血管动脉瘤，并阐明其在cAMP信号中的作用（AIM 2）。总体而言，我们将测试单个纤毛是否可以作为响应式PDE/CAMP的关键传感器车厢。