Repair, Regeneration and Fibrosis of the Salivary Gland

唾液腺的修复、再生和纤维化

• 批准号: 9098687
• 负责人: MARIA A. KUKURUZINSKA
• 金额: $ 19.98万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098687
• 关键词: Ablation; Adult; Apoptosis; Autoimmune Diseases; Biological Models; Bone Marrow; Cataract Extraction; Cell Lineage; Cell Nucleus; Cells; Characteristics; Coupled; Deglutition; Development; Disease; Duct (organ) structure; Economic Burden; Embryo; Environment; Epithelium; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Future; Genetic; Gland; Goals; Head and Neck Cancer; Healed; Health; Homeostasis; Induction of Apoptosis; Injury; Investigation; Knowledge; Ligation; Link; Literature; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Stem Cells; Mesoderm; Modeling; Morbidity - disease rate; Morphogenesis; Mus; Muscle; Myofibroblast; Natural regeneration; Nature; Opportunistic Infections; Oral; Pericytes; Phenotype; Physiology; Play; Prevention; Process; Radiation; Radiation therapy; Recruitment Activity; Role; Salivary; Salivary Gland Diseases; Salivary Glands; Signal Transduction; Site; Sjogren' s Syndrome; Skin; Source; Stem cells; Structural defect; Structure; Submandibular gland; System; Tamoxifen; Testing; Therapeutic; Tissues; Transgenic Mice; Translating; Vimentin; Wound Healing; Xerostomia; cell type; clinically relevant; design; disorder prevention; healing; health economics; in vivo; in vivo Model; injured; injury and repair; innovation; insight; lens; novel; prevent; progenitor; promoter; repaired; response; response to injury; stem cell therapy; tissue regeneration; tissue repair; translational study; wound

 DESCRIPTION (provided by applicant): Salivary gland dysfunctions that accompany disease states pose a substantial health and economic burden in the US and worldwide. The debilitating consequences of radiation treatment for head and neck cancer, and of the autoimmune disorder Sjögren's Syndrome (SS), could be ameliorated with effective strategies to regenerate functional salivary epithelia and to prevent the development of fibrosis. The goal of this exploratory R21 proposal is to generate new knowledge about salivary gland repair and prevention of disease-associated fibrosis. Our preliminary studies identified a novel subpopulation of vimentin-rich cells within the SMG epithelia. These cells underwent expansion in response to injury and functioned in wound repair. They closely resembled vimentin-rich repair cell progenitors of mesodermal lineage within the lens epithelia that mediate injury repair, and whose ablation results in ineffective repair of the epithelium. Importantly, when these repair cells encounter a rigid extracellular matrix environment characteristic of injured tissues, they ca differentiate into fibrotic disease-causing myofibroblasts. Since diseases of the salivary glands result in structural defects, they are likely to trigger the repair process that involves activatio of these vinmentin-rich repair cells. In this proposal, we aim to characterize the SMG repair cells and to elucidate their role in SMG repair, including their ability to acquire myofibroblast phenotypes when the healing process is complete. Our hypothesis is that repair cell progenitors of mesodermal lineage in the SMG function as immediate responders to injury, that they mediate effective wound repair and that their fates include elimination by apoptosis and differentiation into myofibroblasts. We will test this hypothesis using genetic lineage tracing in transgenic mice that express a tamoxifen-inducible CreER under control of the endogenous vimentin promoter, coupled with ex vivo and in vivo SMG injury models. Two aims are proposed: 1) investigate the lineage of SMG repair cells, their response to injury, and the cell signaling and cytoskeletal functions essential to their reparative function; and 2) determine the fate of the repair cells following wound healing, including their ability to cause fibrotic disease Our proposed studies are significant and innovative because they will determine the identity of the SMG repair cells and explore whether these mesenchymal cells can potentially serve in salivary tissue regeneration. In addition, we will gain knowledge into how to manipulate these repair cells to prevent the development of salivary gland fibrotic disease. Our findings have the potential to be translated into effective therapeutic approaches for the regeneration of salivary gland structure and function, and to the fields of tissue injury repair and regeneration, in genera.

 描述（由申请人提供）：伴随疾病状态的唾液腺功能障碍在美国和全世界造成巨大的健康和经济负担。放射治疗对头颈癌和自身免疫性疾病干燥综合征（SS）造成的衰弱后果可以通过再生功能性唾液上皮细胞和防止纤维化发展的有效策略得到改善。这项探索性 R21 提案的目标是产生有关唾液腺修复和预防疾病相关纤维化的新知识。我们的初步研究在 SMG 上皮细胞内发现了一种富含波形蛋白的新细胞亚群。这些细胞因损伤而发生扩张，并在伤口修复中发挥作用。它们与晶状体上皮内富含波形蛋白的修复细胞祖细胞非常相似，可介导损伤修复， 其消融导致上皮修复无效。重要的是，当这些修复细胞遇到受损组织特有的刚性细胞外基质环境时，它们可以分化为引起纤维化疾病的肌成纤维细胞。由于唾液腺疾病会导致结构缺陷，因此它们可能会触发修复过程，其中涉及激活这些富含长纹素的修复细胞。在本提案中，我们的目标是表征 SMG 修复细胞并阐明它们在 SMG 修复中的作用，包括它们在愈合过程完成时获得肌成纤维细胞表型的能力。我们的假设是，SMG 中中胚层谱系的修复细胞祖细胞作为损伤的直接反应者，介导有效的伤口修复，并且它们的命运包括通过细胞凋亡消除和分化为肌成纤维细胞。我们将使用转基因小鼠的遗传谱系追踪来检验这一假设，这些转基因小鼠在内源性波形蛋白启动子的控制下表达他莫昔芬诱导的 CreER，并结合离体和体内 SMG 损伤模型。提出了两个目标：1）研究 SMG 修复细胞的谱系、它们对损伤的反应以及对其修复功能至关重要的细胞信号传导和细胞骨架功能； 2) 确定伤口愈合后修复细胞的命运，包括它们引起纤维化疾病的能力。我们提出的研究具有重要意义和创新性，因为它们将确定 SMG 修复细胞的身份，并探索这些间充质细胞是否有可能在唾液组织再生中发挥作用。此外，我们还将了解如何操纵这些修复细胞来预防唾液腺纤维化疾病的发展。我们的研究结果有可能转化为唾液腺结构和功能再生的有效治疗方法，以及组织损伤修复和再生领域。