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

描述（由申请人提供）：口腔-面部-手指综合征1型（OFD1）和多囊肾病（PKD）经常同时出现在人类患者中。共同的病理可能与共同通路的缺陷有关。OFD1，就像越来越多的与颅面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起作用。初级纤毛是一种类似天线的细胞器，在器官发育和功能的调节中起着至关重要的作用。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。已发表的文献假设OFD1通过保守的运输机制靶向口腔源性成牙细胞和肾上皮细胞的初级纤毛，并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将确定OFD1靶向成牙细胞和肾上皮初级纤毛的机制，使用的方法是解剖OFD1的时空运输，并评估对已知纤毛运输成分的依赖性。目的2将评估OFD1在特殊纤毛信号域的组装和膜蛋白的相互作用。本研究首次将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，这些关键纤毛蛋白在相关人类细胞类型中缺陷会导致颅面和肾脏疾病。结果将提供新的信息，蛋白质是如何传递和功能组织在这个细胞位置。研究结果与新墨西哥州的人群有关，那里的一些颅面疾病显示出明显更高的患病率，可能是由于独特的种族和遗传因素。应用新的方法来监测纤毛蛋白的时空运输及其组装到不同的微域，有望验证新的和高度定量的方法来研究纤毛蛋白的运输、组织和功能。总之，这些贡献是重要的，因为它们有可能确定不同细胞类型中纤毛蛋白之间的共性，并确定可能在长期内用于开发新的治疗干预措施，以增强蛋白质靶向到细胞的正确位置。

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.