Clinical Research of Oral Connective Tissue Program

口腔结缔组织项目临床研究

• 批准号: 10244803
• 负责人: Martha Somerman
• 金额: $ 17.88万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10244803
• 关键词: Affect; Age; Alkaline Phosphatase; Ankylosis; Binding; C-terminal; Cells; Cementocyte; Cementogenesis; Cervical; Chicago; Clinical; Clinical Research; Collaborations; Connective Tissue; Data; Defect; Dental; Dental Cementum; Dental Enamel; Dentin; Development; Diagnosis; Diphosphates; Disease; Dysplasia; Epigenetic Process; Exhibits; Extramural Activities; Familial tumoral calcinosis; Fostering; Gene Proteins; Genes; Genetic Predisposition to Disease; Histologic; Histology; Human; Hypoxia Inducible Factor; Individual; Institutional Review Boards; Knockout Mice; Lead; Maintenance; Manuscripts; Maryland; Mathematics; Medical History; Metabolic Diseases; Metabolism; Minerals; Molecular Analysis; Mutation; National Institute of Dental and Craniofacial Research; Natural regeneration; New Jersey; Newborn Infant; North Carolina; Ohio; Oral; Orthodontic; Osteoclasts; Osteolysis; Pathology; Patients; Pattern; Phenotype; Proteins; Protocols documentation; Publications; Publishing; RANK protein; Recording of previous events; Reporting; Research Personnel; Roentgen Rays; Root Resorption; Saliva; Sampling; School Dentistry; Skeleton; Structure; Thick; Tissues; Tooth Movement; Tooth root structure; Tooth structure; United States National Institutes of Health; Universities; Work; arterial calcification of infancy; base; bone; craniofacial complex; deciduous tooth; density; exome sequencing; extracellular; gene function; human subject; inorganic phosphate; kindred; loss of function mutation; member; microCT; microbial; mineralization; novel; plasma cell membrane glycoprotein PC-1; programs; repaired; skeletal

Project A. Determine genetic susceptibility and immunopathological mechanisms contributing to idiopathic tooth root resorption Background: Previously, we reported that BSP KO mice exhibit a tooth root resorption phenotype. Based on this finding, we sought to identify human subjects exhibiting multiple idiopathic cervical root resorption (MICRR), a familial pattern of MICRR with suggested genetic susceptibility. Following IRB approval from the University of Detroit Mercy School of Dentistry and NIH, dental/medical histories, x-rays, saliva samples, and extracted teeth were collected from a kindred (4 affected and 4 unaffected members) exhibiting MICRR. Whole exome sequencing using saliva identified a mutation in the c-terminal region of IRF8 responsible for overactive osteoclast function. Results were published in JBMR, 2019 and this project transitioned to University Maryland with Dr. Thumbigere-Math (K99/R00 recipient). Ongoing: We continue to collaborate with Dr. Thumbigere-Math as the lead on the IRF8 project, with other NIH collaborators, Drs. Ozato and Holland, with a publication in Bone, 2020 (see below). Collaborations were established with other clinicians: Dr. Steve Russo (Chicago, IL), Dr. Thomas Schneider (New Jersey), and Dr. Janina Golob Deeb (VCU), who have seen patients with rapid MICRR. Dr. Golob Deeb noticed a potential association with MICRR and cessation of denosumab, leading us to collaborate with Drs. Alison Boyce and Marie Kao-Hseih (NIDCR) to conduct dental exams on patients taking denosumab for fibrous dysplasia. We have also set up a collaboration with an expert in microbial analyses, Dr. Purnima Kumar (Ohio State University), to determine the microbial profile of plaque samples from Russos patient. Further, we analyzed teeth obtained from Dr. Betty Hajishengallis (U. Penn), from a patient with missing ossicles and idiopathic root resorption, diagnosed with familial expansile osteolysis (age 10, mutations in the TNFRSF11 gene encoding RANK protein, over expression) and noted cementum defects. Project B. Disorders of mineralization: In collaboration with NIDCR clinical researchers and other IC clinicians, we have been examining individuals with mineralized tissue metabolism disorders for alterations in tissues/cells of the DOC complex. 1. Mutations in key regulators of Pi/PPi. Mineralization of skeleton and teeth is tightly regulated by levels of extracellular inorganic phosphate (Pi) and pyrophosphate (PPi). Three regulators that control pericellular concentrations of Pi and PPi include tissue-nonspecific alkaline phosphatase (TNAP), progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Inactivation of these factors results in mineralization disorders affecting teeth and their supporting structures. We examined the effect of decreased PPi on development and maturation of teeth in human subjects (4) with generalized arterial calcification of infancy (GACI), who harbor loss-of-function mutations in ENPP1. Subjects reported a history of infraocclusion or over-retained primary teeth,poor orthodontic tooth movement, suggesting altered mineral metabolism as a contributing factor. Micro-CT analyses of extracted primary teeth from GACI subjects revealed marked increase cervical cementum thickness and density vs. age-matched healthy control teeth. There were no differences in enamel and dentin densities between GACI and control teeth. Histology revealed dramatically expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. Micro-CT analysis of Enpp1 knock-out mouse molars revealed a marked increase in acellular cementum thickness and volume. Collectively, these findings report a novel dental phenotype in GACI and further support our hypothesis that Pi/PPi modulation is as a key mechanism for regulating cementogenesis across species. Thumbigere-Math V et al., JDR, 2018. Ongoing: We have continued to examine patients with Pi/PPi disorders at NIH CRC as well as analyzing exfoliated or extracted teeth from patients with Pi/PPi disorders. We have also included patients with ABCC6 (ATP Binding Cassette Subfamily C Member 6), which is associated with some cases of GACI. We have also been examining teeth from patients with disorders associated with skeletal disturbances, e.g., human familial tumoral calcinosis (collaborators: Dr. Michael Collins, manuscript submitted July 2020) , patients with Hypoxia-inducible factor 2a mutations (collaborators: Drs. Pacak, Rosenblum, and Zhuang). For controls, in collaboration with North Carolina State University and Duke under the Newborn Epigenetics Study, we are obtaining exfoliated primary teeth from healthy individuals.

项目A.确定遗传敏感性和免疫病理学机制有助于特发性牙根吸收 背景：以前，我们报道了BSP KO小鼠表现出牙根吸收表型。基于这一发现，我们试图确定表现出多种特发性宫颈根吸收（MICRR）的人类受试者，这是一种具有建议的遗传易感性的MICRR的家族模式。在IRB获得了底特律Mercy大学牙科和NIH的IRB批准之后，牙科/医学历史，X射线，唾液样本和拔牙是从一名（有4个受影响和4个未受影响的成员）的MICRR中收集的。使用唾液的整个外显子组测序鉴定了负责过度活跃破骨细胞功能的IRF8的C末端区域的突变。结果发表在JBMR，2019年，该项目与Thumbigere-Math博士（K99/R00接收者）过渡到马里兰州。 正在进行中：我们继续与Thumbigere-Math博士合作，作为IRF8项目的负责人，其他NIH合作者Drs。 Ozato和Holland，在骨头上发表了2020年的出版物（见下文）。与其他临床医生建立了合作：史蒂夫·鲁索（Steve Russo）博士（伊利诺伊州芝加哥），托马斯·施耐德（Thomas Schneider）（新泽西州）和Janina Golob Deeb（VCU）博士，他们曾见过快速MICRR患者。 戈洛布·迪布（Golob Deeb）博士注意到与MICRR的潜在关联和Denosumab停止，导致我们与Drs合作。艾莉森·博伊斯（Alison Boyce）和玛丽·考赫（Marie Kao-Hseih）（NIDCR）对服用denosumab患有纤维发育不良的患者进行牙科检查。 我们还与微生物分析专家Purnima Kumar（俄亥俄州立大学）建立了合作，以确定Russos患者的斑块样品的微生物概况。此外，我们分析了从贝蒂·哈吉·汉加利斯博士（U. Penn）获得的牙齿，该牙齿从丢失的耳囊和特发性根吸收的患者中，被诊断出患有家族性膨胀骨溶解（年龄10，TNFRSF11基因的突变，编码秩蛋白的TNFRSF11中的突变，表达过多）和著名的水泥缺陷。 B.矿化疾病： 与NIDCR临床研究人员和其他IC临床医生合作，我们一直在研究患有矿化组织代谢障碍的人，以改变DOC复合物的组织/细胞。 1。PI/PPI关键调节剂中的突变。骨骼和牙齿的矿化由细胞外无机磷酸盐（PI）和焦磷酸盐（PPI）的水平严格调节。 控制PI和PPI的细胞周围浓度的三个调节剂包括非特异性碱性磷酸酶（TNAP），进行性癌细胞障碍蛋白（ANK）和ecton核苷酸吡咯磷酸酶/磷酸磷酸酯酶1（ENPP1）。 这些因素的失活导致影响牙齿及其支撑结构的矿化障碍。 我们检查了PPI降低对人类受试者（4）中牙齿发育和成熟的影响（婴儿期的广义动脉钙化（GACI）），后者在ENPP1中具有功能丧失突变。 受试者报道了斜牙或原发性过度牙齿的病史，正畸牙齿运动较差，这表明矿物质代谢改变是一个因素。 对GACI受试者提取的原发牙的微分离分析显示，明显增加了颈骨厚度和密度与年龄匹配的健康对照牙齿的增加。 GACI和对照牙齿之间的搪瓷和牙本质密度没有差异。 组织学揭示了GACI牙齿中的宫颈牙骨质大幅扩展，包括胶质细胞样细胞和牙骨质吸收和修复的异常模式。 ENPP1敲除小鼠磨牙的Micro-CT分析表明，细胞牙骨质厚度和体积明显增加。 总的来说，这些发现报告了GACI中一种新型的牙型表型，并进一步支持了我们的假设，即PI/PPI调制是调节整个物种胶结发生的关键机制。 Thumbigere-Math V等，JDR，2018年。 正在进行：我们继续检查NIH CRC的PI/PPI疾病患者，并分析PI/PPI疾病患者的去角质或提取牙齿。 我们还包括患有ABCC6的患者（ATP结合纸盒亚家族C成员6），这与某些GACI相关。 我们还一直在检查与骨骼障碍有关的疾病患者的牙齿，例如人类家族性肿瘤钙化病（合作者：迈克尔·柯林斯博士，手稿于2020年7月提交），缺氧因子2a突变（合作者：PacakDrs。Pacak，Rosenblum和Zhuang）。 对于对照组，根据新生儿表观遗传学研究，与北卡罗来纳州立大学和杜克大学合作，我们正在从健康个体中获得剥落的原发性牙齿。