Regulation of Gastric and Osteoclat Acidification by Snx10

Snx10 对胃酸和骨酸化的调节

基本信息

批准号：
10467087
负责人：
Ricardo Anibal Battaglino
金额：
$ 19.69万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2021-09-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467087
关键词：
Ablation Acids Age-Related Bone Loss Albers-Schonberg disease Binding Blindness Bone Development Bone Diseases Bone Resorption Calcium Calcium Gluconate Candidate Disease Gene Cells Cessation of life Childhood Clinical Complex Defect Development Dextrans Diagnosis Dietary Calcium Dietary Supplementation Disease Early Endosome Endocytosis Endosomes Epithelial Excision Exhibits Facial paralysis Failure Family Family member Fracture GTP Binding Gastric Parietal Cells Gastrointestinal tract structure General Population Genes Genetic Genetic Diseases Goals Golgi Apparatus Homeostasis Human Hypocalcemia result Impairment Intestines Knockout Mice Life Link Longevity Maintenance Mediating Membrane Membrane Proteins Mental Retardation Molecular Mus Mutation Osteoclasts Osteoporosis Outcome Parietal Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Phospholipids Play Production Protein Family Protein Sortings Proteins Recycling Regulation Research Rickets Role Savings Secretory Vesicles Severities Skeletal system Sorting - Cell Movement Specificity Stomach TNFSF11 gene TNFSF5 gene Technology Thinness Vesicle Work base bone bone health bone loss bone mass calcium absorption calcium supplementation cell type deafness economic impact gastrointestinal system health economics improved in vivo infancy infant death intestinal homeostasis mineralization mortality mouse model novel premature prevent protein complex protein transport public health relevance sorting nexins trafficking uptake vesicle transport

项目摘要

DESCRIPTION (provided by applicant): The health and economic impact of osteoporosis continues to make studies of bone resorption by osteoclasts a critically important research focus. Osteoclasts are exceptionally dependent on vesicular trafficking, which is essential for bone resorption. Consequently, disruption (genetic or pharmacological) of osteoclastic vesicle transport abolishes resorptive activity. Proteins of the Snx family are known to mediate endosomal sorting, endocytosis, recycling of membrane proteins, and trafficking between various endosomes and Golgi apparatus. We found Snx10, a family member expressed in osteoclasts and in the stomach, where it is required for acid production. We generated Snx10-deficient mice (Snx10ins/ins) via gene-trap technology and characterized the bone phenotype. Snx10ins/ins mice exhibit a complex phenotype that is a combination of osteopetrosis (due to impaired osteoclast resorption) and rickets (impaired mineralization due to impaired gastric acidification and poor calcium absorption) known as osteopetrorickets. The underlying mechanisms leading to osteopetrorickets are currently unknown. Based on these findings, we conclude that Snx10 is essential for bone homeostasis in vivo by regulating vesicular trafficking and therefore acid production in both osteoclasts and the stomach. In this proposal we will use cell-specific Snx10 ablation studies in bone and stomach to elucidate the molecular mechanisms by which Snx10 regulates both osteoclastic resorption and gastric acidification for bone homeostasis. This proposal has high significance as it will characterize a new candidate gene involved in the development of human bone diseases, including osteoporosis, and bone loss associated with calcium deficiency. These results will change the paradigm of therapy for osteopetrotic patients with mutations in Snx10 and other genes with similar patterns of expression and activities, whose gastric defect has been generally overlooked. Importantly, our findings will significantly advance our understanding of the molecular mechanisms controlling osteoclast function and the control of bone homeostasis by the gastrointestinal tract.

描述（由适用提供）：骨质疏松症的健康和经济影响继续通过破骨细胞研究骨骼解决骨骼，这是至关重要的研究重点。破骨细胞特别取决于囊泡运输，这对于骨骼分辨至关重要。因此，破骨囊泡转运的破坏（遗传或药理）消除了吸收活性。众所周知，SNX家族的蛋白质是内体分选，内吞作用，膜蛋白的回收以及各种内体和高尔基体之间的运输。我们发现SNX10是在破骨细胞和摊位中表达的家庭成员，在那里需要酸产生酸。我们通过基因陷阱技术生成了SNX10缺陷小鼠（SNX10INS/ins），并表征了骨表型。 SNX10INS/INS小鼠表现出复杂的表型，该表型是骨质倍率（由于骨细胞分辨率受损）和rick骨（由于胃酸损伤而受损的矿化受损，钙吸收率降低引起的矿化受损，钙吸收率降低）。目前尚不清楚导致破骨术的基本机制。基于这些发现，我们包含SNX10对体内骨体内平衡至关重要，可以调节囊泡运输，从而在破骨细胞和胃中产生酸。在此提案中，我们将在骨和胃中使用细胞特异性的SNX10消融研究来阐明SNX10调节骨稳态的分子机制。该建议具有很高的意义，因为它将表征与人骨疾病发展有关的新候选基因，包括骨质疏松症，以及与钙缺乏症相关的骨质流失。这些结果将改变SNX10突变和其他具有相似表达和活动模式的基因的骨质原晶患者的治疗范式，其胃缺陷通常被忽略了。重要的是，我们的发现将显着提高我们对控制破骨细胞功能的分子机制以及胃肠道对骨体内稳态的控制。