Characterization of OGFRL1 Knockout Mice

OGFRL1 敲除小鼠的表征

基本信息

批准号：
10361562
负责人：
Yasuyoshi Ueki
金额：
$ 23.78万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361562
关键词：
Adaptor Signaling Protein Address Affect Bone Diseases Bone Resorption Cell Line Cell physiology Cells Cherubism Cytosine Data Defect Disease Dysplasia Etiology Exons Frameshift Mutation Genes Genetic Goals Human Impairment India Inflammatory Investigation Jaw Knock-in Mouse Knockout Mice Lead Lesion Ligature Macrophage Activation Mandible Maxilla Modeling Molecular Mus Mutation Myeloid Cells Nonsense Codon Online Mendelian Inheritance In Man Osteoclasts Pathogenicity Pathologic Pathway interactions Patients Periodontal Diseases Periodontitis Phenotype Physiology Predisposition Production Protein Binding Domain Proteins Rare Diseases Rheumatoid Arthritis Role SH3 Domains Syria TNF gene TRANCE protein Thymine Transgenic Mice alveolar bone bone bone loss bone mass consanguineous family craniofacial exome sequencing gain of function mutation genetic approach in vivo inflammatory bone loss innovation insight joint destruction knock-down loss of function loss of function mutation macrophage member methionine-enkephalin receptor monocyte mouse model novel osteoclastogenesis prevent tartrate-resistant acid phosphatase treatment strategy

项目摘要

The study of rare diseases has provided insights into normal human physiology and has led to strategies to prevent and treat common diseases. Cherubism (OMIM#118400) is an autosomal dominant form of fibrous dysplasia of the jaws characterized by maxillary and mandibular bone destruction caused by fibrous- inflammatory lesions. Currently, SH3-domain binding protein 2 (SH3BP2) is the only gene responsible for cherubism. However, we have identified new autosomal recessive cherubism patients who do not have mutations in SH3BP2 in consanguineous families from Syria and India. To identify novel cherubism genes, we performed whole exome sequencing and discovered homozygous loss-of-function mutations in the opioid growth factor receptor-like 1 (OGFRL1) gene of the affected members. Preliminary results showed that OGFRL1-knockdown increases cellular sensitivity to increase TNF-alpha production in a monocyte/macrophage cell line RAW264.7. The knockdown RAW264.7 cells also showed increased responsiveness to the receptor activator of nuclear factor-kappa B ligand (RANKL), resulting in increased formation of osteoclasts. Therefore, we propose that OGFRL1 is a novel negative regulator of macrophage activation and osteoclast differentiation to regulate the susceptibility to bone loss. Our overall hypothesis is that loss-of-function of OGFRL1 is responsible for a recessive form of cherubism and that OGFRL1 has yet unknown functions in regulating bone mass. Specific aims are: Aim 1) Determine whether OGFRL1 knockout mice recapitulate the phenotype of humans with OGFRL1 mutations. Aim 2) Determine whether OGFRL1 regulates bone loss in a periodontitis model. Aim 3) Determine whether OGFRL1 regulates bone loss in a rheumatoid arthritis model. We will establish OGFRL1 as a new gene responsible for cherubism and explore whether OGFRL1 is a new regulator of bone resorption in common inflammatory bone diseases. These studies will provide new insights into the etiology of cherubism and identify new pathways for the treatment of periodontal diseases and rheumatoid arthritis.

对罕见疾病的研究提供了对正常人类生理学的见解，并产生了治疗策略预防和治疗常见疾病。 Cherubism (OMIM#118400) 是纤维性的常染色体显性形式颌骨发育不良，其特征是由纤维引起的上颌骨和下颌骨破坏炎症性病变。目前，SH3 结构域结合蛋白 2 (SH3BP2) 是唯一负责天使主义。然而，我们发现了新的常染色体隐性遗传天使病患者，他们没有来自叙利亚和印度的近亲家庭中的 SH3BP2 突变。为了识别新的天使基因，我们进行全外显子组测序并发现阿片类药物中的纯合功能丧失突变受影响成员的生长因子受体样 1 (OGFRL1) 基因。初步结果表明 OGFRL1 敲低可增加细胞敏感性，从而增加 TNF-α 的产生单核细胞/巨噬细胞系RAW264.7。敲低的 RAW264.7 细胞也显示出增加对核因子 kappa B 配体 (RANKL) 受体激活剂的反应性，导致破骨细胞的形成。因此，我们提出OGFRL1是一种新型的巨噬细胞负调节因子激活和破骨细胞分化来调节骨质流失的易感性。我们的总体假设是 OGFRL1 的功能丧失导致了隐性形式的天使性，并且 OGFRL1 尚未发现调节骨量的未知功能。具体目标是：目标 1) 确定 OGFRL1 是否被敲除小鼠重现了具有 OGFRL1 突变的人类表型。目标 2) 确定 OGFRL1 是否调节牙周炎模型中的骨丢失。目标 3) 确定 OGFRL1 是否调节骨丢失类风湿性关节炎模型。我们将建立OGFRL1作为负责天使的新基因并探索 OGFRL1是否是常见炎症性骨病中骨吸收的新调节因子。这些研究将为小天使的病因学提供新的见解，并确定治疗小天使的新途径牙周病和类风湿性关节炎。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

OC_Finder: Osteoclast segmentation, counting, and classification using watershed and deep learning.

OC_Finder：使用分水岭和深度学习进行破骨细胞分割、计数和分类。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Wang, Xiao;Kittaka, Mizuho;He, Yilin;Zhang, Yiwei;Ueki, Yasuyoshi;Kihara, Daisuke
通讯作者：
Kihara, Daisuke

Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model.

在小鼠天使模型中，伊马替尼对炎症和骨质减少表型的影响很小。

DOI：
发表时间：
2023-04
期刊：
影响因子：
3.8
作者：
Mukai, Tomoyuki;Akagi, Takahiko;Hiramatsu Asano, Sumie;Tosa, Ikue;Ono, Mitsuaki;Kittaka, Mizuho;Ueki, Yasuyoshi;Yahagi, Ayano;Iseki, Masanori;Oohashi, Toshitaka;Ishihara, Katsuhiko;Morita, Yoshitaka
通讯作者：
Morita, Yoshitaka