Regulation of SMG Development by Adhesion Receptors

粘附受体对 SMG 发育的调节

• 批准号: 7623595
• 负责人: MARIA A. KUKURUZINSKA
• 金额: $ 32.62万
• 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/7623595
• 关键词: 1-Phosphatidylinositol 3-Kinase; 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(申请人提供)：这项研究的长期目标是阐明细胞-细胞和细胞-基质黏附受体在调节唾液腺颌下腺(SMG)发育中的作用。SMG的发育是通过分支形态发生，从上皮芽发育成树状结构，由一系列导管组成，末端是分泌腺泡。SMG形态发生涉及生长和新芽形成的周期，这些周期与导管结构的扩张和分支紧密协调。引导腺泡和导管前体细胞分化为有组织的三维结构的调控信号在很大程度上是未知的。由于细胞-细胞和细胞-基质的相互作用已被证明在上皮组织发育过程中调节形态发生的变化，我们主要关注唾液细胞-细胞黏附受体E-钙粘附素和层粘连蛋白的受体1321整合素，层粘连蛋白是SMG基底膜的主要成分。我们的研究表明，腺泡和导管细胞的命运模式是在初芽阶段建立的，并在整个形态发生过程中保持。腺泡祖细胞局限于与基底膜接触的外周细胞层，而内芽细胞包括增殖性导管祖细胞和非增殖性分化导管细胞。E-钙粘附素是这些细胞在SMG形态发生过程中发挥多种功能所必需的。在腺泡前体细胞中，E-钙粘素连接通过与1321整合素的相互作用而稳定，从而调节腺泡前体细胞增殖与新芽形成的协调。在肾细胞中也发现了类似的稳定E-钙粘蛋白连接的机制，其中1321整合素组织多蛋白支架。我们的研究还表明，大量产生增殖的导管前体细胞通过Src的活性维持未成熟的E-钙粘素连接。在后来的形态发生中，Src似乎被磷酸酶、SHP2和/或PTP的招募所抵消，以促进导管的形成。在导管发育过程中，稳定的E-钙粘蛋白连接信号分化和保护细胞免受细胞凋亡的死亡很可能是通过激活PI3K/Akt途径实现的。我们的假设是，E-钙粘附素在SMG形态发生和分化的不同方面的功能受结构和信号分子的调节。我们建议通过研究SMG形态发生过程中不同细胞群中E-钙粘附素黏附活性变化的机制来检验这一假说，目的有三：1)检测1321整合素是否通过招募支架蛋白来稳定腺泡前体细胞中的E-钙粘附素连接；2)检测SMG生长与导管细胞分化的协调是否涉及Src对E-钙粘蛋白功能的调节以及随后从E-钙粘附素连接到PI3激酶的信号转导；以及3)验证蛋白磷酸酶调节发育中SMG唾液细胞成熟过程中E-钙粘附素细胞-细胞接触的假说。唾液腺疾病，包括癌症和干燥综合征，以细胞-基质和细胞-细胞黏附的破坏为特征。我们的研究重点是细胞-细胞和细胞-基质黏附受体的功能及其在唾液腺发育过程中的调控。了解这些黏附受体如何驱动形态发生事件，对于设计针对患病唾液组织的有效疗法以及唾液腺生物工程和组织置换至关重要。