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

• 批准号: 10647751
• 负责人: Surya Nauli
• 金额: $ 34.5万
• 依托单位: CHAPMAN UNIVERSITY
• 依托单位国家: 美国
• 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/10647751
• 关键词: Adult; Aneurysm; Blood Vessels; Cell Compartmentation; Cell physiology; Cells; Centrosome; 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; Medical; Modeling; Molecular; Mus; Mutation; Nanotechnology; Organelles; Pathway interactions; Patients; 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; genetic approach; imaging system; improved; in vivo; inhibitor; knock-down; malformation; mouse model; nano; nanoparticle; nanoparticle drug; novel; novel strategies; pharmacologic; phosphoric diester hydrolase; prevent; public health relevance; response; sensor; small hairpin RNA; spatiotemporal; therapeutic target; tool

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 环磷酸腺苷（cAMP）信号调节不同的途径和细胞功能， 在具体的反应时，当划分。然而，cAMP在纤毛功能中的作用知之甚少， 尽管cAMP在纤毛病变的发展中起作用。使用两种新技术，纳米粒子 药物输送和单细胞成像系统，我们的初步数据表明，cAMP的变化， 纤毛可以独立于胞质中的纤毛。此外，我们有初步证据表明，抑制 磷酸二酯酶-3（PDE 3），一种cAMP的灭活剂，可以恢复睫状体病模型中的纤毛功能， 易发生动脉瘤，动脉瘤血管的特征是基因组不稳定。我们假设 睫状环磷酸腺苷在动脉瘤形成中起重要作用，我们建议测试PDE 3是否参与动脉瘤形成。 血管瘤通过基因组不稳定性（Aim 1），并阐明其在初级纤毛cAMP信号转导中的作用（Aim 2）。总的来说，我们将测试的想法，如果一个单一的纤毛可能是一个关键的传感器作为一个响应PDE/cAMP 车厢