Angiocrine Factors in Salivary Gland Regeneration

唾液腺再生中的血管分泌因子

• 批准号: 10516728
• 负责人: Amber Altrieth
• 金额: $ 1.46万
• 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 2023-04-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516728
• 关键词: Acinar Cell; Angiogenic Factor; Atrophic; Autoimmune Diseases; BMP5 gene; Biological Assay; Blood Vessels; Bone Marrow; Cell Death; Cell Line; Cell Proliferation; Cell secretion; Cells; Clinical; Clip; Coculture Techniques; Defect; Disease; Duct (organ) structure; Educational process of instructing; Endothelial Cells; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Excision; Extracellular Matrix; FDA approved; Fibronectins; Functional disorder; Future; Gland; Growth; Growth Factor; Head and Neck Cancer; Health; Homeostasis; Human; Impairment; Infiltration; Inflammatory; Injury; 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; Proliferating; 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; comparison control; density; 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： 唾液功能减退或唾液流量减少是自身免疫性疾病引起的常见病症 干燥综合症、治疗头颈癌的放射疗法以及副作用 药物。唾液腺功能减退会导致营养、牙齿和心理健康方面的困难， 导致生活质量下降。目前的治疗方案仅是姑息治疗和新的再生治疗 需要治疗。再生是组织在受伤或损伤后的生长、更新或恢复。 不同生物体的再生能力各不相同，哺乳动物的再生能力在很大程度上受到限制。学习 下颌下唾液腺的再生，我们将采用导管结扎模型，其中腺体 结扎两周后萎缩，由于腺泡细胞死亡而导致腺体重量减少 分泌颗粒的损失。去除夹子或结扎后，颌下唾液腺会再生， 由于腺泡细胞增殖和分泌颗粒的恢复，腺体重量增加。大多数研究 使用导管结扎模型重点关注腺泡细胞的作用，因为它们在产生 唾液;然而，排列在血管内表面的内皮细胞对于血管的再生至关重要。 其他器官。尽管内皮细胞功能障碍与干燥综合征患者的一部分有关 以及接受放射治疗作为头颈癌治疗的患者，内皮细胞如何 对唾液腺功能和修复能力的贡献尚不清楚。内皮细胞在以下过程中发挥着关键作用 通过分泌旁分泌因子来实现器官发育、稳态和再生，包括 生长因子、形态发生素、细胞外基质成分和作用于上皮细胞的趋化因子， 这些因子统称为血管分泌因子。血管分泌因子信号传导已被证明 器官特异性，在再生期间变化，并且随着再生时间过程而改变。 然而，下颌下唾液腺在体内平衡过程中产生的血管分泌因子 再生尚未定义。使用导管结扎模型，我将分析产生的血管分泌因子 与结扎两周相比，结扎三天和六天后内皮细胞的变化 手术控制腺体。 RNA-seq 将用于鉴定由以下物质产生的血管分泌因子靶标： 积极再生唾液内皮细胞。三天和六天后上皮细胞的微阵列分析 去连接将用于识别血管分泌因子受体表达的潜在变化。击倒和 过表达慢病毒构建体将用于离体以确定这些假定的贡献 唾液腺类器官中的血管分泌因子并确定可能的作用机制。定义 血管分泌因子在再生过程中的作用机制将有助于更好地理解 未来唾液腺功能恢复的可能方法。本次培训计划还将准备 我希望以教授的身份从事研究和教学工作。