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.

摘要