Mitochondrial respiration as a regulator of lymphatic cell fate and therapeutic lymphangiogenesis

线粒体呼吸作为淋巴细胞命运和治疗性淋巴管生成的调节剂

基本信息

批准号：
10640152
负责人：
GUILLERMO C OLIVER
金额：
$ 77.1万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640152
关键词：
Adult Angiogenesis Inhibitors Birth Blood Blood Vessels Cardiac Myocytes Cardiovascular Diseases Cell Cycle Cell Differentiation process Cell Line Cell Proliferation Cell physiology Cells Cellular Metabolic Process Chemicals Complex DNA Damage Data Development Disease Electron Transport Electron Transport Complex III Embryo Embryonic Development Endothelial Cells Exhibits Fibrosis Glycolysis Growth Health Heart Heart Injuries Heterogeneity Hybrids In Vitro Infarction Inflammation Injections Injury Ischemia Knowledge Lymph Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphocyte Maintenance Malonates Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Mouse Strains Mus Mutant Strains Mice Myocardial Infarction Natural regeneration Neonatal Organ Organelles Oxidative Phosphorylation Oxidoreductase Pathologic Physiological Process Production Proliferating Reactive Oxygen Species Regenerative capacity Regenerative response Regulation Respiration Role Route Signal Transduction Specific qualifier value Structure of sinus venosus of sclera Succinate Dehydrogenase Succinates Therapeutic Therapeutic Uses Tissues Vascular Diseases Vascularization Work acute pancreatitis alternative oxidase angiogenesis cardiac regeneration cardiac repair cardioprotection cell fate specification chronic pancreatitis genomic locus heart function immune clearance improved in vivo insight kidney medulla lymphatic vasculature lymphatic vessel mitochondrial metabolism mouse model neonatal mice nervous system disorder novel strategies organ repair overexpression paracrine postnatal prevent sensor tissue injury vascular bed

项目摘要

Summary Endothelial cell (EC) metabolism has emerged as an essential driver and regulator of blood and lymphatic vessel development, as well as an alternative approach in anti-angiogenic therapy. It has been shown that metabolism is not only vital to EC function, but also to controlling different steps of the (lymph)-angiogenic process. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Our recent findings revealed that by sensing the lymphatic endothelial cell (LEC) differentiation status and microenvironmental metabolic conditions, mitochondrial complex III regulates LEC fate specification and maintenance during embryonic development. Similar to what was shown for blood endothelial cells, most likely in different pathological conditions, mitochondrial respiration is also required for the growth and expansion (lymphangiogenesis) of lymphatics. We argue that mitochondrial respiration sensing and regulation of the metabolic status of LECs is a critical step during developmental and disease-promoted lymphangiogenesis, and we will evaluate this proposal in mouse models of cardiac injury and induced acute and chronic pancreatitis.

概括内皮细胞（EC）代谢已成为血液和淋巴管的重要驱动力和调节器血管发育，以及抗血管生成治疗的替代方法。事实证明代谢不仅对 EC 功能至关重要，而且对控制（淋巴）血管生成的不同步骤也至关重要过程。淋巴管表现出显着的可塑性和异质性，反映了它们的功能专门控制组织微环境。我们最近的研究结果表明，通过感知淋巴管内皮细胞（LEC）分化状态和微环境代谢条件、线粒体复合体 III 调节胚胎发育过程中 LEC 的命运规范和维持。类似于什么显示了血液内皮细胞，很可能在不同的病理条件下，线粒体呼吸淋巴管的生长和扩张（淋巴管生成）也需要它。我们认为线粒体 LEC 代谢状态的呼吸感知和调节是发育和发育过程中的关键步骤疾病促进的淋巴管生成，我们将在小鼠心脏损伤模型和诱发急、慢性胰腺炎。