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.

项目概要肥胖是一种全球流行病，也是美国一些主要死亡原因的主要原因，包括糖尿病、心脏病、中风和某些类型的癌症。肥胖在多种代谢中发挥着多效性作用过程，包括全身能量代谢。维持全身稳态涉及协调多个组织的代谢过程，包括脂肪组织和骨骼。鉴于其突出的在多个身体过程中发挥作用，最近的证据表明骨骼在全身能量中发挥着重要作用代谢。骨髓来源的细胞，特别是巨噬细胞，已被确定为髓外脂肪组织由源自骨髓的造血干细胞产生。骨细胞构成超过 90% 的骨细胞，是机械传感器和骨重塑过程的协调者。骨细胞连接蛋白 43 (Ocy Cx43) 是一种在骨中表达的跨膜蛋白，可形成半通道（HC）促进细胞之间以及与环境的沟通。假设 Ocy Cx43 可能在脂肪组织的调节以及由此产生的代谢和疾病进展，从未被研究过。通过使用表达显性失活 Cx43 的转基因小鼠骨细胞或单克隆抗体中的突变体可打开/关闭 Cx43 HC，我们的实验室已证明 Ocy Cx43 HC 负责脂肪形成的变化，与骨髓细胞的调节相关人口。因此，改变 Ocy Cx43 活性可能成为治疗代谢性疾病的新治疗靶点。疾病，包括肥胖。这项研究工作旨在了解 Ocy Cx43 HC 如何改善代谢通过骨髓细胞调节减少脂肪来保持健康，并将其评估为对抗肥胖的独特目标。这些信息将确定肥胖和代谢疾病的新治疗靶点。更好的理解连接这些组织/细胞的潜在机制将使我们能够操纵这些组织/细胞改善全身能量代谢和葡萄糖稳态，并对抗脂肪形成的环境。