Regulation of SMG Development by Adhesion Receptors

粘附受体对 SMG 发育的调节

• 批准号: 8064728
• 负责人: MARIA A. KUKURUZINSKA
• 金额: $ 31.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064728
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acinar Cell; Acinus organ component; Adhesions; Adhesives; Apoptotic; Basement membrane; Biomedical Engineering; Cadherins; Cell Communication; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell physiology; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Cessation of life; Competence; Complex; Cytoskeleton; Development; Distal; Duct (organ) structure; Ductal; Ductal Epithelial Cell; E-Cadherin; Embryo; Epithelial; Epithelial Cells; Event; Exhibits; Extracellular Matrix; Goals; Growth; Integrins; Kidney; Laminin Receptor; Lateral; Lead; Maintenance; Malignant Neoplasms; Mediating; Morphogenesis; Non-Receptor Type 11 Protein Tyrosine Phosphatase; Pathway interactions; Pattern; Peripheral; Phosphoric Monoester Hydrolases; Play; Population; Proliferating; Protein phosphatase; Publishing; Regulation; Role; Salivary; Salivary Gland Diseases; Salivary Gland Tissue; Salivary Glands; Scaffolding Protein; Signal Transduction; Signaling Molecule; Sjogren' s Syndrome; Staging; Stem cells; Structure; Submandibular gland; Surface; Testing; Therapeutic; Time; Tissues; Trees; Work; adhesion receptor; base; design; gland development; human PHEMX protein; kidney cell; mouse development; new growth; premature; progenitor; response; salivary cell; scaffold; src-Family Kinases; three dimensional structure

DESCRIPTION (provided by applicant): The long term goal of this study is to elucidate the roles of cell-cell and cell-matrix adhesion receptors in the regulation of the salivary submandibular gland (SMG) development. SMG develops through branching morphogenesis from an epithelial bud into a tree-like structure consisting of an array of ducts terminating in secretory acini. SMG morphogenesis involves cycles of growth and new bud formation that are tightly coordinated with the expansion and branching of ductal structures. The regulatory signals that guide the specification, expansion and differentiation of acinar and ductal progenitors into an organized three dimensional structure are largely unknown. Because cell-cell and cell-matrix interactions have been shown to regulate morphogenetic changes during epithelial tissue development, we have focused on E-cadherin, a principal salivary cell-cell adhesion receptor, and 1321 integrin, the receptor for laminin, a major component of the basement membrane in the SMG. Our studies have shown that the patterns of acinar and ductal cell fate are established at the initial bud stage and maintained throughout morphogenesis. Acinar progenitors are restricted to the peripheral cell layer in contact with the basement membrane, while the interior bud cells comprise proliferating ductal progenitors and non-proliferating differentiating duct cells. E-cadherin is required for diverse functions of these cells during SMG morphogenesis. In the acinar progenitor cells, E-cadherin junctions are stabilized through the interaction with 1321 integrin to regulate the coordination of acinar progenitor cell proliferation with new bud formation. Similar mechanism for stabilization of E-cadherin junctions is found in renal cells, where 1321 integrin organizes multiprotein scaffolds. Our studies also show that the mass producing proliferating ductal progenitors maintain immature E-cadherin junctions by the activity of Src. Later in morphogenesis, Src appears to be counteracted by the recruitment of phosphatases, SHP2 and/or PTP< to promote duct formation. During duct development, stable E-cadherin junctions signal differentiation and protection from apoptotic death most likely through the activation of PI3K/Akt pathway. Our hypothesis is that E-cadherin-mediated functions in different aspects of SMG morphogenesis and differentiation are regulated by association with structural and signaling molecules. We propose to test this hypothesis by investigating the mechanisms underlying changes in E-cadherin adhesive activity in distinct cell populations during SMG morphogenesis in three aims: 1) examine whether 1321 integrin stabilizes E-cadherin junctions in the acinar progenitor cells through the recruitment of scaffold proteins; 2) examine if coordination of SMG growth with ductal cell differentiation involves regulation of E-cadherin function by Src and subsequent signaling from E-cadherin junctions to PI3 kinase; and 3) examine the hypothesis that protein phosphatases regulate E-cadherin cell-cell contacts during maturation of salivary cells in the developing SMG. Diseases of the salivary glands, including cancer and Sjogren's Syndrome, are characterized by the disruption of cell-matrix and cell-cell adhesion. Our studies focus on the functions of cell-cell and cell-matrix adhesion receptors and their regulation during salivary gland development. Understanding how these adhesion receptors drive morphogenetic events is essential for the design of effective therapeutics that will target diseased salivary tissues, as well as for the bioengineering of salivary glands and tissue replacement.

描述（由申请人提供）：这项研究的长期目标是阐明细胞细胞和细胞 - 基质粘附受体在调节唾液下颌腺（SMG）发育中的作用。 SMG通过将形态发生从上皮芽分支形态发生发展成一个树状结构，该结构由终止分泌acini的一系列管道组成。 SMG形态发生涉及生长周期和新的芽形成，这些周期与导管结构的扩展和分支紧密协调。指导腺泡和导管祖细胞向有组织的三维结构的规范，扩展和分化的调节信号在很大程度上尚不清楚。由于已显示细胞 - 细胞和细胞矩阵相互作用可以调节上皮组织发育过程中的形态发生变化，因此我们集中于E-钙粘着蛋白，一种主要的唾液细胞 - 细胞粘附受体，1321整合素，层粘连蛋白的受体，层粘连蛋白，SMG中基层膜的主要成分。我们的研究表明，腺泡和导管细胞命运的模式是在初始芽阶段建立的，并保持了整个形态发生。腺泡祖细胞仅限于与基底膜接触的外围细胞层，而内部芽细胞包含增殖的导管祖细胞和非增殖的分化导管细胞。在SMG形态发生过程中，这些细胞的各种功能需要E-钙粘着蛋白。在腺泡祖细胞中，通过与1321整联蛋白的相互作用来稳定电子钙粘蛋白连接蛋白，以调节腺泡祖细胞细胞增殖与新芽形成的配位。在肾细胞中发现了稳定E-钙粘着蛋白连接的类似机制，其中1321个整合素组织了多蛋白支架。我们的研究还表明，产生增殖的导管祖细胞通过SRC的活性维持未成熟的电子钙粘着蛋白连接。在形态发生的后期，SRC似乎被磷酸酶SHP2和/或PTP <募集以促进导管形成所抵消。在管道发育过程中，稳定的E-钙粘着蛋白连接蛋白连接信号分化和免受凋亡死亡的保护，最有可能通过PI3K/AKT途径的激活而进行。我们的假设是，在SMG形态发生和分化不同方面的E-钙粘蛋白介导的功能通过与结构和信号分子的关联来调节。我们建议通过研究SMG形态发生期间E-钙粘蛋白粘附活性的基本变化的机制来检验这一假设，这三个目的：1）检查1321是否通过募集ca虫蛋白的募集来检查1321是否稳定腺泡祖细胞中的E-钙粘着蛋白连接蛋白； 2）检查SMG生长与导管细胞分化的配位是否涉及通过SRC调节E-钙粘蛋白功能以及随后从E-钙粘着蛋白连接蛋白到PI3激酶的信号传导； 3）检查以下假设：蛋白质磷酸酶在发育中的SMG中调节唾液细胞成熟期间调节电子钙粘蛋白细胞 - 细胞接触。唾液腺的疾病，包括癌症和sjogren综合征，其特征在于细胞 - 矩阵和细胞细胞粘附的破坏。我们的研究集中于细胞细胞和细胞 - 基质粘附受体的功能及其在唾液腺发育过程中的调节。了解这些粘附受体如何驱动形态发生事件对于将靶向患病的唾液组织以及唾液腺和替代组织的生物工程设计的有效治疗剂的设计至关重要。