Signaling at the primary cilium in development and disease

发育和疾病中初级纤毛的信号传导

• 批准号: 10330492
• 负责人: Saikat Mukhopadhyay
• 金额: $ 32.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330492
• 关键词: Address; Adenylate Cyclase; Affect; Cilia; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyst; Development; Disease; Embryology; Erinaceidae; Functional disorder; Homeostasis; Human; Human Genetics; Kidney; Microtubules; Morphogenesis; Morphology; Nephrology; Neural Tube Closure; Neural tube; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Phenotype; Process; Property; Proteomics; Regulation; Repression; Research; Role; Signal Transduction; Signaling Molecule; Testing; Tissues; Tubular formation; Vertebrates; Work; appendage; base; cell type; ciliopathy; extracellular; innovation; insight; morphogens; mouse model; neuropathology; preservation; prevent; public health relevance; response; smoothened signaling pathway; trafficking

Abstract The primary cilium is a microtubule-based dynamic cellular appendage that is found in many cell types. Cilia transduce cellular responses to extracellular signals, particularly to the morphogen hedgehog in vertebrates during differentiation and proliferation, regulating morphogenesis in multiple tissues. However, the mechanisms by which cilia-specific signals are maintained and propagated to direct downstream pathways during morphogenesis is not well understood. Understanding signaling at cilia requires mechanistic understanding of trafficking to cilia, isolating ciliary from extraciliary functions of signaling molecules, and studying functional consequences directly in tissues without disrupting cilia. My group is one of the foremost in studying cilia-specific signaling from subcellular to organismal scales, while preserving ciliary morphology. We identified the ciliary trafficking adapter Tulp3 and key repressors of hedgehog pathway, Gpr161 and Ankmy2, both of which function via cAMP signaling regulated by cilia. We postulate that the inherent complexity of ciliary signaling can be understood by examining how signals are maintained in and propagated uniquely by cilia (compartmentalization) and how cilia direct positive and negative regulation in downstream pathways (counterregulatory signaling). Over the next five years, we will directly study how compartmentalization and counterregulatory signaling at cilia regulates morphogenesis in different tissues. By leveraging our expertise in ciliary trafficking and hedgehog pathway repression, and by using innovative mouse models, we will study the effect of ciliary signaling in the following contexts. First, we will determine how counterregulatory signaling in cilia regulates renal tubular homeostasis. We hypothesize that Tulp3 cargoes function as cystogenic ciliary signals that are normally inhibited by polycystins. We propose to identify cystogenic drivers in cilia by identifying and perturbing cargoes of Tulp3 in preventing cysts. Second, we will determine the role of ciliary cAMP signaling in neural tube patterning and closure. We hypothesize that hedgehog pathway repression by cAMP-protein kinase A signaling at cilia regulates neural tube closure. We will determine role of adenylyl cyclase and protein kinase A compartmentalization in the cilium-centrosomal complex in regulating hedgehog signaling strength, neural tube patterning, and closure. Third, we will determine how cilia regulated repression of hedgehog pathway affects tissue morphogenesis. We will test ciliary contributions to repression thresholds required for specific morpho-phenotypic outcomes by perturbing ciliary compartmentalization of Gpr161 and adenylyl cyclases. Through this research we will identify the features and consequences distinctive to signaling by cilia in directing tissue emergent properties. Our work is cross-disciplinary and is supported by collaborators with expertise in proteomics, nephrology, neuropathology, human genetics and embryology. Our research will expose new entry points for understanding complex ciliopathy phenotypes and define translational opportunities for treating diseases caused by ciliary dysfunction.

抽象的 原发性纤毛是一种基于微管的动态细胞附件，在许多细胞类型中都发现。纤毛 对细胞外信号的细胞反应，特别是对脊椎动物的形态基因刺猬的反应 在分化和增殖过程中，调节多个组织中的形态发生。但是，机制 通过其中维持和传播纤毛特异性的信号在下游途径。 形态发生尚不清楚。了解纤毛的信号需要机械理解 运输到纤毛，从信号分子的外部功能中分离睫状，并研究功能 直接在组织中的后果而不会破坏纤毛。我的小组是研究纤毛特异性的最重要的 从亚细胞到有机尺度的信号传导，同时保留睫状形态。我们确定了睫状 贩运适配器Tulp3和Hedgehog Pathway，GPR161和Ankmy2的主要阻遏物，这两个功能 通过cilia调节的cAMP信号。我们假设睫状信号的固有复杂性可以是 通过检查信号如何维持和通过纤毛独特地传播（分隔）来理解 以及纤毛在下游途径中如何直接正向调节（反调节信号传导）。超过 接下来的五年，我们将直接研究纤毛的分隔和反调节信号如何 调节不同组织中的形态发生。通过利用我们在睫毛贩运和刺猬方面的专业知识 途径抑制，通过使用创新的小鼠模型，我们将研究睫状信号在 以下上下文。首先，我们将确定纤毛中的反调节信号如何调节肾小管 稳态。我们假设Tulp3货物起着通常被抑制的膀胱源性睫状信号 由polycystins。我们建议通过识别和扰动tulp3的货物来识别纤毛中的囊肿驱动器 预防囊肿。其次，我们将确定睫状营信号在神经管形成和 关闭。我们假设Camp蛋白激酶A信号在Cilia调节的刺猬途径抑制 神经管闭合。我们将确定腺苷酸环化酶和蛋白激酶的作用 纤毛中心伦敦复合物在调节刺猬信号传导强度，神经管图案和闭合方面。 第三，我们将确定纤毛调节刺猬途径的抑制如何影响组织形态发生。我们 将测试针对特定形态表型结果所需的抑制阈值的睫状贡献 GPR161和腺苷循环酶的纤毛隔室化。通过这项研究，我们将确定 纤毛在指导组织新兴特性中的信号传导的特征和后果。我们的工作 是跨学科的，得到了​​具有蛋白质组学，肾脏病，神经病理学专业知识的合作者的支持 人类遗传学和胚胎学。我们的研究将揭示新的入口点以了解复杂 纤毛病表型和定义了由睫状功能障碍引起的疾病的转化机会。