Regulation of SMG Development by Adhesion Receptors

粘附受体对 SMG 发育的调节

• 批准号: 7932547
• 负责人: MARIA A. KUKURUZINSKA
• 金额: $ 1.49万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932547
• 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（由申请方提供）：本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下腺（SMG）发育中的作用。SMG通过分支形态发生从上皮芽发育成树状结构，该树状结构由终止于分泌腺泡的导管阵列组成。SMG形态发生涉及与导管结构的扩张和分支紧密协调的生长和新芽形成的周期。引导腺泡和导管祖细胞特化、扩增和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，我们集中在E-钙粘蛋白，一个主要的唾液细胞-细胞粘附受体，和1321整合素，层粘连蛋白的受体，SMG中的基底膜的主要组成部分。我们的研究表明，腺泡和导管细胞的命运模式建立在最初的芽阶段，并保持整个形态发生。腺泡祖细胞局限于与基底膜接触的外周细胞层，而内部芽细胞包括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都需要E-钙粘蛋白。在腺泡祖细胞中，E-cadherin连接通过与1321整合素的相互作用来稳定，以调节腺泡祖细胞增殖与新芽形成的协调。在肾细胞中发现了E-钙粘蛋白连接稳定的类似机制，其中1321整合素组织多蛋白支架。我们的研究还表明，大量产生的增殖的导管祖细胞通过Src的活性维持不成熟的E-钙粘蛋白连接。在形态发生后期，Src似乎被磷酸酶、SHP 2和/或PTP的募集抵消以促进导管形成。在导管发育期间，稳定的E-钙粘蛋白连接信号分化和保护免于凋亡死亡最可能通过PI 3 K/Akt通路的激活。我们的假设是，E-钙粘蛋白介导的SMG形态发生和分化的不同方面的功能调节协会与结构和信号分子。我们拟通过研究SMG形态发生过程中不同细胞群体中E-cadherin粘附活性变化的机制来验证这一假设，目的有三：1）检测1321整合素是否通过募集支架蛋白来稳定腺泡祖细胞中的E-cadherin连接; 2）检查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-钙粘蛋白连接到PI 3激酶的信号传导;以及3）检验蛋白磷酸酶在发育中的SMG中的唾液细胞成熟期间调节E-钙粘蛋白细胞-细胞接触的假设。唾液腺疾病，包括癌症和干燥综合征，其特征在于细胞-基质和细胞-细胞粘附的破坏。我们的研究主要集中在细胞-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设计针对患病唾液组织的有效疗法以及唾液腺和组织替代的生物工程至关重要。