Osteocytic Connexin 43 Hemichannel Regulation of Adiposity

骨细胞连接蛋白 43 半通道对肥胖的调节

• 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
• 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

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.

项目总结 肥胖是一种全球流行病，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。肥胖在多种代谢过程中起着多效性作用。 过程，包括全身能量新陈代谢。维持全身动态平衡涉及到 多个组织中代谢过程的协调，包括脂肪组织和骨骼。鉴于其突出的 在多个身体过程中的作用，最近的证据表明骨骼在全身能量中起着重要的作用 新陈代谢。髓系细胞，特别是巨噬细胞，已被确认为 髓外脂肪组织，起源于骨髓的造血干细胞。骨细胞 包括90%的骨细胞，是骨重建过程的机械传感器和管弦乐团。 骨细胞连接蛋白43(OCY Cx43)是一种在骨骼中表达的跨膜蛋白，可形成半角突 (HCS)，促进细胞之间以及细胞与环境之间的交流。假设 Ocy Cx43可能在脂肪组织的调节中起关键作用，从而在新陈代谢和 疾病的进展，从未被调查过。利用表达显性负性Cx43的转基因小鼠 在骨细胞或打开/关闭Cx43 HC的单抗中的突变体，我们的实验室已经证明Ocy Cx43HC负责脂肪形成的变化，与髓系细胞的调制相关 人口。因此，改变Ocy Cx43活性可能成为治疗代谢疾病的新靶点。 疾病，包括肥胖。这项研究旨在了解Ocy Cx43 HCS如何改善代谢 通过调节髓系细胞来减少脂肪，并将其作为抗击肥胖的独特目标进行评估。 这些信息将确定肥胖症和代谢性疾病的新治疗目标。更好地理解 连接这些组织/细胞的潜在机制将使我们有能力操纵这些 改善全身能量代谢和葡萄糖动态平衡的环境，并对抗脂肪形成。