Angiocrine Factors in Salivary Gland Regeneration

唾液腺再生中的血管分泌因子

• 批准号: 10311050
• 负责人: Amber Altrieth
• 金额: $ 3.22万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311050
• 关键词: Acinar Cell; Angiogenic Factor; Atrophic; Autoimmune Diseases; BMP5 gene; Biological Assay; Blood Vessels; Bone Marrow; Cell Death; Cell Line; Cell Proliferation; Cells; Clinical; Clip; Coculture Techniques; Defect; Disease; Duct (organ) structure; Educational process of instructing; Endothelial Cells; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Excision; Extracellular Matrix; FDA approved; Fibronectins; Functional disorder; Future; Gland; Growth; Growth Factor; Head and Neck Cancer; Health; Homeostasis; Human; Impairment; Inflammatory; Injury; Lead; Ligation; Link; Liver; Liver Regeneration; Mental Health; Microarray Analysis; Modeling; Morphogenesis; Mus; Natural regeneration; Nutritional; Operative Surgical Procedures; Oral; Oral health; Organ; Organism; Organoids; Patients; Pharmaceutical Preparations; Play; Population; Production; Quality of life; Radiation therapy; Regenerative Medicine; Regenerative research; Regenerative response; Research; Resected; Role; Saliva; Salivary; Salivary Glands; Scientist; Secretory Vesicles; Signal Transduction; Sjogren' s Syndrome; Stimulant; Sublingual Gland; Submandibular gland; Surface; Surgical Models; Surgical incisions; System; Time; Tissues; Training; Training Programs; Weight; Xerostomia; career; chemokine; differential expression; effective therapy; functional restoration; head and neck cancer patient; insight; knock-down; mRNA sequencing; morphogens; organ growth; overexpression; palliative; paracrine; patient subsets; professor; psychologic; receptor; receptor expression; regenerative; regenerative therapy; repaired; response to injury; restoration; side effect; tissue injury; transcriptome; transcriptome sequencing

Abstract: Salivary hypofunction, or reduced saliva flow, is a common condition resulting from the autoimmune disease Sjögren’s Syndrome, radiation therapy for treatment of head and neck cancer, and side effects of medications. Salivary hypofunction can lead to difficulties with nutritional, dental, and psychological health, leading to a decreased quality of life. Current treatment options are only palliative and new regenerative therapies are needed. Regeneration is the growth, renewal, or restoration of tissue following injury or damage. Regenerative ability varies among organisms, with mammalian regeneration being largely limited. To study regeneration of the submandibular salivary gland we will employ a ductal ligation model in which the gland atrophies following a two-week ligation, resulting in a decrease in gland weight due to acinar cell death and loss of secretory granules. After clip removal, or deligation, the submandibular salivary gland regenerates, increasing in gland weight, due to acinar cell proliferation and restoration of secretory granules. Most studies using the ductal ligation model have focused on the role of the acinar cells due to their importance in producing saliva; however, endothelial cells that line the interior surface of blood vessels are critical for regeneration of other organs. Although endothelial cell dysfunction has been linked to a subset of Sjögren’s Syndrome patients as well as patients receiving radiation therapy as a treatment for head and neck cancer, how endothelial cells contribute to salivary gland function and repair capacity is not understood. Endothelial cells play critical roles in organ development, homeostasis, and regeneration through the secretion of paracrine factors, including growth factors, morphogens, extracellular matrix components, and chemokines that act on epithelial cells, which are collectively referred to as angiocrine factors. Angiocrine factor signaling has been shown to be organ-specific, to vary during times of regeneration, and to change over the time course of regeneration. However, angiocrine factors produced by the submandibular salivary gland during homeostasis and regeneration have not been defined. Using the ductal ligation model, I will profile angiocrine factors produced by endothelial cells after three and six days of deligation in comparison to two weeks of ligation relative to surgical control glands. RNA-seq will be used to identify the angiocrine factor targets that are produced by actively regenerating salivary endothelial cells. Microarray analysis of epithelial cells after three and six days deligation will be used to identify potential changes in angiocrine factor receptor expression. Knockdown and overexpression lentiviral constructs will be used ex vivo to determine the contribution of these putative angiocrine factors in salivary gland organoids and to identify possible mechanisms of action. Defining the mechanism of action of the angiocrine factors during regeneration will allow for a better understanding of possible means for future functional restoration of the salivary gland. This training program will also prepare me for a career in research and teaching as a professor.

抽象的： 唾液功能低下或减少唾液流量是由自身免疫引起的常见状况 疾病Sjögren综合征，用于治疗头颈癌的放射治疗以及 药物。唾液功能障碍会导致营养，牙齿和心理健康的困难， 导致生活质量下降。当前的治疗选择只有姑息性和新再生 需要疗法。再生是受伤或损害后组织的生长，更新或恢复。 生物体之间的再生能力变化，哺乳动物的再生在很大程度上受到限制。学习 下颌下唾液腺的再生我们将采用一种导管结扎模型 两周结扎后萎缩，导致腺体细胞死亡和 分泌颗粒的损失。去除夹或算法后，下颌下唾液腺再生， 由于腺泡细胞的增殖和分泌颗粒的恢复，腺体重量增加。大多数研究 使用导管连接模型的重点是腺泡细胞的作用，因为它们在生产中的重要性 唾液;但是，排列血管内部表面的内皮细胞对于再生至关重要 其他器官。尽管内皮细胞功能障碍已与Sjögren综合征患者的一部分有关 以及接受放射疗法作为头颈癌的治疗的患者以及内皮细胞如何 对唾液腺功能和维修能力的贡献尚不清楚。内皮细胞在 通过分泌旁分泌因素，包括 生长因子，形态剂，细胞外基质成分和作用于上皮细胞的趋化因子， 共同称为血管分泌因素。血管分泌因子信号已显示为 特定于器官的，在再生时期的变化，并在再生时间过程中改变。 然而，稳态和下颌下唾液腺产生的血管分泌因子和 尚未定义再生。使用导管连接模型，我将介绍产生的血管分泌因子 相对于两周的连接相比，在划定三天和六天后，由内皮细胞进行 手术控制网格。 RNA-seq将用于识别由血管分泌因子靶标的 积极再生唾液内皮细胞。三天和六天后对上皮细胞的微阵列分析 算法将用于确定血管分泌因子受体表达的潜在变化。敲击和 过表达的慢病毒构建体将在体内使用来确定这些推定的贡献 唾液腺器官中的血管分泌因子并确定可能的作用机理。定义 再生过程中血管分泌因素的作用机制将使您更好地理解 可能的手段用于将来的唾液腺功能恢复。该培训计划也将准备 我从事教授的研究和教学职业。