Osteocytic Connexin 43 Hemichannel Regulation of Adiposity

骨细胞连接蛋白 43 半通道对肥胖的调节

基本信息

批准号：
10606023
负责人：
Francisca Maria Acosta
金额：
$ 7.22万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606023
关键词：
Adipocytes Adipose tissue Aftercare Age American Antibodies Biological Process Biomedical Engineering Bone Marrow Bone remodeling Cause of Death Cell Communication Cell Survival Cells Circulation Communication Connexin 43 Connexins Data Diabetes Mellitus Dinoprostone Disease Disease Progression Distant Dominant-Negative Mutation Energy Metabolism Environment Epidemic Extramedullary Fatty acid glycerol esters Global Change Health Healthcare Heart Diseases Hematopoietic stem cells Homeostasis Integral Membrane Protein Knowledge Laboratories Macrophage Maintenance Mentors Metabolic Metabolic Diseases Metabolism Monitor Monoclonal Antibodies Morbidity - disease rate Mus Myelogenous Myeloid Cells Obesity Obesity Epidemic Organ Osteocytes Outcome Paracrine Communication Physiology Play Population Preparation Process Proteins Regulation Research Role Signal Transduction Site Source Stroke Testing Therapeutic Tissue Expansion Tissues Transgenic Mice Work Writing autocrine blood glucose regulation bone bone cell cancer type career career development combat experience extracellular improved insight mechanotransduction metabolic abnormality assessment mortality mouse model mutant new therapeutic target novel obesity development response skills stem cells therapeutic target transdifferentiation

项目摘要

PROJECT SUMMARY Obesity is a global epidemic and a major contributor to some of the leading causes of death in the U.S., including diabetes, heart disease, stroke, and certain types of cancer. Obesity plays a pleiotropic role in various metabolic processes, including whole-body energy metabolism. Maintenance of whole-body homeostasis involves the coordination of metabolic processes in multiple tissues, including adipose tissue and bone. Given its prominent role in multiple bodily processes, recent evidence points to bone as a significant player in whole-body energy metabolism. Myeloid-derived cells, specifically macrophages, that have been identified as a source of extramedullary adipose tissue, arise from hematopoietic stem cells originating from the bone marrow. Osteocytes comprise >90% of bone cells, are mechanosensors, and orchestrators of the bone remodeling process. Osteocytic connexin 43 (Ocy Cx43) is a transmembrane protein expressed in bone that forms hemichannels (HCs) that facilitate the communication of cells among themselves and with their environment. The postulation that Ocy Cx43 may have a key role in the modulation of adipose tissue, and consequently metabolism and disease progression, has never been investigated. By using transgenic mice expressing dominant-negative Cx43 mutants in osteocytes or monoclonal antibodies that open/close Cx43 HCs, our laboratory has shown that Ocy Cx43 HCs are responsible for changes in adipose formation, in correlation with modulation in myeloid cell populations. Thus, altering Ocy Cx43 activity could be a new therapeutic target for the treatment of metabolic diseases, including obesity. This research effort aims to understand how Ocy Cx43 HCs can improve metabolic health by reducing fat through myeloid cell regulation and evaluate this as a unique target for combatting obesity. This information will identify new therapeutic targets for obesity and metabolic diseases. A better understanding of the underlying mechanism connecting these tissues/cells will give us the ability to manipulate these environments to improve systemic energy metabolism and glucose homeostasis, and to combat fat formation.

项目摘要肥胖是全球流行病，是美国一些主要死亡原因的主要贡献者，包括糖尿病，心脏病，中风和某些类型的癌症。肥胖在各种代谢中起多效性作用过程，包括全身能量代谢。维护全身稳态涉及多种组织中的代谢过程的协调，包括脂肪组织和骨骼。鉴于其突出在多个身体过程中的作用，最近的证据表明骨头是全身能量的重要参与者代谢。粒细胞来源的细胞，特别是巨噬细胞，已被鉴定为造成造血干细胞产生的脂外脂肪组织，源自骨髓。骨细胞骨细胞的> 90％是骨细胞，是机械传感器和骨骼重塑过程的编排者。骨细胞连接蛋白43（OCY CX43）是一种在骨骼中表达的跨膜蛋白，形成半通道（HC）促进细胞之间以及环境之间的交流。该法案 OCY CX43可能在脂肪组织的调节中具有关键作用，因此代谢和疾病进展，从未被研究过。通过使用表达显性阴性CX43的转基因小鼠开放/关闭CX43 HCS的骨细胞或单克隆抗体中的突变体，我们的实验室表明OCY CX43 HCS负责脂肪形成的变化，与髓样细胞中的调节相关人群。因此，改变OCY CX43活性可能是代谢治疗的新治疗靶点疾病，包括肥胖。这项研究工作旨在了解OCY CX43 HCS如何改善代谢通过减少髓样细胞调节脂肪的健康，并将其评估为对抗肥胖症的独特靶标。该信息将确定肥胖和代谢疾病的新治疗靶标。更好的理解连接这些组织/细胞的基本机制将使我们能够操纵这些改善系统性能量代谢和葡萄糖稳态以及对抗脂肪形成的环境。