OFD1 as constituent of a multimeric protein complex in odontoblast primary cilia

描述(由申请人提供)：口腔-面部-指端综合征1型(OFD1)和多囊肾病(PKD)经常同时出现在人类患者中。这些共同的病理很可能与共同通路中的缺陷有关。OFD1与越来越多的与头面部和囊性肾脏疾病相关的蛋白质一样，定位于初级纤毛并在其中发挥功能。初级纤毛是一种触角状细胞器，在器官发育和功能的调节中起着重要的作用。在细胞水平上，这是由于纤毛在调节细胞生长和分化中的机械感觉和信号功能。已发表的文献认为，OFD1通过一种保守的转运机制定位于口腔来源的成牙本质细胞和肾上皮细胞的初级纤毛，在那里它被组织成具有特殊信号功能的膜微域。提出了两个具体目标。目的1研究OFD1在成牙本质细胞和肾上皮细胞中定位于原发纤毛的机制，研究OFD1在纤毛运输中的时空转运机制，并评价纤毛转运对纤毛转运的依赖性。目的2将评估OFD1组装成专门的纤毛信号域和膜蛋白相互作用。这项拟议的研究是首次将OFD1的纤毛传递和膜组织与其他关键纤毛蛋白进行直接比较，当缺陷时，这些纤毛蛋白会导致相关人类细胞类型的头面部和肾脏疾病。这些结果将为蛋白质如何传递到这个细胞位置并在其中进行功能组织提供新的信息。这一结果与新墨西哥州的人群相关，在那里，一些颅面部疾病的患病率明显较高，可能是由于独特的种族和遗传因素。应用新的方法监测纤毛蛋白的时空运输及其组装进入不同的微域，有望验证用于研究纤毛蛋白运输、组织和功能的新的、高度定量的方法。总而言之，这些贡献意义重大，因为它们有可能确定不同细胞类型的纤毛蛋白之间的共性，并确定长期可用于开发新的治疗干预措施的靶点，以增强蛋白质靶向细胞的正确位置。

DESCRIPTION (provided by applicant): Oral-facial-digital syndrome type 1 (OFD1) and polycystic kidney disease (PKD) frequently present together in human patients. The shared pathologies are likely linked to defects in common pathways. OFD1, like a growing list of proteins that are associated with craniofacial and cystic kidney disease, localizes to and functions within the primary cilium. The primary cilium is an antenna-like organelle that is crucia in the regulation of organ development and function. At the cellular level this is due to the mechanosensory and signaling functions of the cilia in regulating cell growth and differentiation. The published literature leads to the hypothesis that OFD1 is targeted to the primary cilium of oral cavity derived odontoblast and renal epithelial cells using a conserved trafficking mechanism where it is organized into membrane microdomains with specialized signaling functions. Two specific aims are proposed. Aim 1 will determine the mechanism by which OFD1 is targeted to the primary cilium in odontoblasts and renal epithelia using methodologies that dissect the spatio-temporal transport of OFD1 and evaluate dependence on known ciliary trafficking components for ciliary delivery. Aim 2 will evaluate the assembly of OFD1 into specialized ciliary signaling domains and membrane protein interactions. The proposed research is the first of its kind to directly compare the ciliary delivery and membrane organization of OFD1 with other key ciliary proteins that when defective result in craniofacial and kidney disorders in the relevant human cell types. The results will provide new information on how proteins are delivered to and functionally organized within this cellular location. The results have relevance to New Mexico's populations where some craniofacial disorders show a significantly higher prevalence possibly due to unique ethnic and genetic factors. The application of novel methodologies for monitoring the spatio-temporal trafficking of ciliary proteins and their assembly into distinct microdomains is expected to validate new and highly quantitative approaches for studying ciliary protein trafficking, organization, and function. Together these contributions are significant because of their potential to determine the commonalities between ciliary proteins in diverse cell types and identify targets that may in the long term be used to develop new therapeutic interventions for enhancing protein targeting to the correct location of the cell.