Determinants of GPCR Ciliary Localization and Effects on Signaling

GPCR 纤毛定位的决定因素及其对信号传导的影响

• 批准号: 8109301
• 负责人: KIRK A MYKYTYN
• 金额: $ 26.46万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109301
• 关键词: Affect; Amino Acids; Bardet-Biedl Syndrome; Biology; Blindness; Brain; Calcium Channel; Cell membrane; Cell physiology; Cells; Cilia; Cognitive deficits; Complex; Congenital neurologic anomalies; Consensus; Cyclic AMP; Cystic Kidney Diseases; Defect; Development; Disease; Failure; Functional disorder; G-Protein-Coupled Receptors; Genetic Models; Goals; Human; Human body; Hyperphagia; Hypogonadism; In Vitro; Kidney Diseases; Knockout Mice; Laboratories; Lead; Limb structure; Liver diseases; Location; Mammalian Cell; Mediating; Membrane; Mental Retardation; Metabolism; Mus; Mutation; Neurons; Obesity; Organelles; Pathogenesis; Phenotype; Process; Proteins; Public Health; Regulation; Research; Resources; Retinal Degeneration; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Sorting - Cell Movement; System; Testing; Time; appendage; base; developmental disease; feeding; insight; melanin-concentrating hormone receptor; novel; protein transport; receptor; serotonin 6 receptor; somatostatin receptor 3; tool; trafficking; voltage

DESCRIPTION (provided by applicant): Primary cilia are solitary appendages that are present on nearly all mammalian cells. Although primary cilia were once considered vestigial, they are now recognized as important cellular sensory and signaling organelles. Defects in the formation or function of primary cilia have been implicated in the pathogenesis of many human developmental disorders and diseases. Yet, the functions of cilia on most cells are unknown. Studies of cilia dysfunction and disease have revealed that the functions of primary cilia are defined by the specific signaling proteins that localize to the membrane of the cilium. These studies have also shown that failure of ciliary signaling proteins to properly localize can lead to disease. However, few ciliary signaling proteins have been identified and the mechanisms that regulate their localization to cilia remain unknown. We have discovered that the genetic defects associated with the human ciliary disorder Bardet-Biedl syndrome (BBS) appear to affect cilia function through a mechanism that disrupts trafficking of G protein-coupled receptors (GPCRs) onto the cilium. Importantly, this finding may represent the fundamental mechanism underlying the pathophysiology of the seemingly diverse BBS phenotypes, including obesity, cognitive deficits, renal cystic disease, and retinal degeneration. The central hypotheses of this proposal are; 1) Ciliary GPCRs contain unique sequences that mediate their localization to cilia, 2) Ciliary localization of GPCRs requires interactions with the BBS proteins, and 3) Mislocalization of ciliary receptors in BBS alters signaling and leads to disease The objectives of this application are to define the intramolecular determinants of GPCR ciliary localization and use this information to identify novel ciliary signaling pathways, define the intermolecular determinants of GPCR ciliary localization and the mechanism(s) by which BBS proteins regulate this process, and determine the effects of ciliary GPCR mislocalization on signaling. These studies will lend valuable insight into the trafficking of ciliary GPCRs and will be used to predict novel ciliary GPCRs. Understanding the determinants and mechanisms of ciliary localization and the effects of a lack of ciliary localization on signaling is essential to elucidating the functions of these organelles and determining their roles in development and disease. PUBLIC HEALTH REVELANCE: Although it is known that almost every cell in the human body possesses an important sensory and signaling appendage called a primary cilium, the functions of cilia on most cells are unknown. The importance of these organelles is highlighted by the fact that defects in primary cilia have been associated with developmental disorders and diseases, including; obesity, renal disease, blindness, nervous system abnormalities, mental retardation, liver disease, and limb defects. The results obtained from the proposed studies will provide important insights into the mechanisms that control the localization of specific signaling proteins to cilia and how disruptions in these mechanisms affect signaling.

描述(申请人提供)：初级纤毛是存在于几乎所有哺乳动物细胞上的孤立附属物。虽然初级纤毛曾经被认为是退化的，但现在它们被认为是重要的细胞感觉和信号细胞器。初级纤毛的形成或功能缺陷与许多人类发育障碍和疾病的发病机制有关。然而，纤毛在大多数细胞上的功能尚不清楚。对纤毛功能障碍和疾病的研究表明，初级纤毛的功能是由定位于纤毛膜的特定信号蛋白决定的。这些研究还表明，纤毛信号蛋白未能正确定位可能会导致疾病。然而，几乎没有纤毛信号蛋白被鉴定出来，并且调节它们定位到纤毛的机制仍然不清楚。我们发现，与人类纤毛疾病Bardet-Biedl综合征(BBS)相关的遗传缺陷似乎通过破坏G蛋白偶联受体(GPCRs)到纤毛的运输来影响纤毛功能。重要的是，这一发现可能代表了看似不同的BBS表型的基本病理生理机制，包括肥胖、认知缺陷、肾囊性疾病和视网膜变性。该方案的核心假设是：1)纤毛GPCRs含有独特的序列，介导其纤毛定位；2)纤毛定位需要与BBS蛋白相互作用；3)纤毛受体在BBS中的错误定位改变了信号转导并导致疾病。本研究的目的是确定纤毛定位的分子内决定因素，并利用这些信息识别新的纤毛信号通路，确定纤毛定位的分子间决定因素和BBS蛋白调节这一过程的机制(S)，并确定纤毛GPCR误定位对信号的影响。这些研究将为纤毛GPCRs的贩运提供有价值的见解，并将用于预测新的纤毛GPCRs。了解纤毛定位的决定因素和机制，以及纤毛定位缺失对信号的影响，对于阐明这些细胞器的功能并确定它们在发育和疾病中的作用是至关重要的。 公共卫生评论：虽然已知人体中几乎每个细胞都有一个重要的感觉和信号附件，称为初级纤毛，但纤毛在大多数细胞上的功能尚不清楚。初级纤毛的缺陷与发育障碍和疾病有关，包括肥胖、肾脏疾病、失明、神经系统异常、智力低下、肝脏疾病和肢体缺陷，这一事实突显了这些细胞器的重要性。从拟议的研究中获得的结果将为控制特定信号蛋白对纤毛的定位的机制以及这些机制中的干扰如何影响信号提供重要的见解。