The Regulation of Salivary Gland Regeneration by P2Y2 Nucleotide Receptors

P2Y2核苷酸受体对唾液腺再生的调控

• 批准号: 7932509
• 负责人: GARY Andrew WEISMAN
• 金额: $ 20万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932509
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acinar Cell; Acinus organ component; Actins; Autoimmune Diseases; Bladder; C10; Cartilage; Cell Adhesion Molecules; Cell Differentiation process; Cell Proliferation; Cell surface; Cells; Complex; Cytoskeletal Proteins; Cytoskeleton; DNA Sequence Rearrangement; Disease; Duct (organ) structure; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Event; Extracellular Signal Regulated Kinases; Gland; Goals; Growth Factor Receptors; Head and Neck Cancer; Integrin Binding; Integrin Signaling Pathway; Integrins; Ligands; Ligation; Maintenance; Mediating; Metalloproteases; Mitogen-Activated Protein Kinases; Modeling; Natural regeneration; Nucleotides; Parotid Gland; Pathway interactions; Phospholipase C; Proteins; Publishing; RGD (sequence); Receptor Activation; Receptor Signaling; Recovery; Regenerative Medicine; Regulation; Resistance; Role; Salivary; Salivary Gland Tissue; Salivary Glands; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Skin; Structure; Submandibular gland; Techniques; Tight Junctions; Tissues; Transactivation; Wound Healing; bone; cell growth; cell motility; corneal epithelium; design; filamin; gland development; human disease; in vitro Model; in vivo; injured; irradiation; migration; monolayer; novel; novel strategies; nucleotide receptor; public health relevance; receptor; receptor binding; receptor coupling; receptor upregulation; regenerative; repaired; response; saliva secretion; tissue regeneration

DESCRIPTION (provided by applicant): Regenerative medicine represents an exciting new approach in the treatment of human disease. Progress has been made in strategies for the regeneration of a variety of tissues including skin, corneal epithelium, cartilage, bone and bladder. Tissue regeneration would represent an important advancement in the treatment of salivary gland hypofunction that occurs in the autoimmune disease Sjogren's syndrome and as a result of 3-irradiation therapies for head and neck cancers. To develop techniques for the successful regeneration of salivary glands in vivo, it is first necessary to understand signaling pathways that regulate gland development, which involves acinar formation (i.e., cell proliferation and migration) and organization of acini into a functional gland structure (i.e., cell differentiation into a polarized epithelium with high transepithelial resistance). Towards the goal of regenerating salivary gland tissue, our studies have identified a P2Y2 nucleotide receptor (P2Y2R) that is upregulated in diseased or damaged salivary glands. These published and preliminary findings have demonstrated that P2Y2R activation regulates signaling pathways that mediate cell proliferation and migration and the maintenance of tight junctions required for normal saliva secretion. Over the past 15 years, we have identified novel structural motifs in the P2Y2R that facilitate interactions with complex signaling networks known to regulate cell growth and differentiation involving integrins, growth factor receptors, matrix metalloproteases, adhesion molecules and cytoskeletal proteins. These signaling networks enable the P2Y2R to regulate cellular responses, including migration and proliferation, integrin/extracellular matrix interactions, cytoskeletal rearrangements and the expression of cell adhesion molecules and tight junction proteins. Collectively, these results strongly support the hypothesis that expression and activation of P2Y2Rs in damaged or diseased salivary gland epithelium promote tissue repair and regeneration. Accordingly, we propose to utilize in vitro models of acinar formation to demonstrate that activation of P2Y2Rs enhances regenerative responses. We also will use in vivo submandibular gland (SMG) duct-ligation to validate a role for P2Y2Rs in the recovery and regeneration of damaged salivary glands. We have organized these hypotheses around several Specific Aims. Specific Aim 1 will identify P2Y2R signaling pathways that mediate acinar formation. Specific Aim 2 will investigate the role of integrin/P2Y2R interactions in cellular responses required for acinar formation. Specific Aim 3 will determine whether P2Y2R interaction with the actin cytoskeleton regulates tight junction organization in Par-C10 monolayers. The 3 Specific Aims in this proposal are designed to identify the mechanisms whereby P2Y2R upregulation and activation enhances salivary gland regeneration towards developing better therapies to repair damaged salivary glands. PUBLIC HEALTH RELEVANCE: Salivary glands are damaged by diseases such as Sjogren's syndrome and as a result of 3-irradiation therapies for head and neck cancers. Our studies have identified a receptor on the cell surface, the P2Y2 nucleotide receptor (P2Y2R) that is upregulated in diseased or damaged salivary glands. Previous studies have demonstrated that P2Y2R activation regulates signaling pathways that mediate cell proliferation, migration and differentiation, which strongly support the hypothesis that expression and activation of P2Y2Rs in damaged or diseased salivary glands can be used to promote tissue repair and regeneration.

描述（由申请人提供）：再生医学代表了治疗人类疾病的一种令人兴奋的新方法。包括皮肤、角膜上皮、软骨、骨骼和膀胱在内的多种组织的再生策略已取得进展。组织再生将代表治疗因自身免疫性疾病干燥综合征以及头颈癌 3 次放射治疗导致的唾液腺功能减退的重要进展。为了开发体内唾液腺成功再生的技术，首先有必要了解调节腺体发育的信号通路，其中涉及腺泡形成（即细胞增殖和迁移）和将腺泡组织成功能性腺体结构（即，细胞分化为具有高跨上皮电阻的极化上皮）。为了实现唾液腺组织再生的目标，我们的研究发现了一种 P2Y2 核苷酸受体 (P2Y2R)，它在患病或受损的唾液腺中表达上调。这些已发表的初步研究结果表明，P2Y2R 激活可调节信号通路，介导细胞增殖和迁移以及维持正常唾液分泌所需的紧密连接。在过去的 15 年里，我们在 P2Y2R 中发现了新的结构基序，这些基序促进了与复杂信号网络的相互作用，这些信号网络已知调节细胞生长和分化，涉及整合素、生长因子受体、基质金属蛋白酶、粘附分子和细胞骨架蛋白。这些信号网络使 P2Y2R 能够调节细胞反应，包括迁移和增殖、整合素/细胞外基质相互作用、细胞骨架重排以及细胞粘附分子和紧密连接蛋白的表达。总的来说，这些结果有力地支持了以下假设：受损或患病唾液腺上皮中 P2Y2R 的表达和激活可促进组织修复和再生。因此，我们建议利用腺泡形成的体外模型来证明 P2Y2R 的激活增强再生反应。我们还将使用体内颌下腺 (SMG) 导管结扎来验证 P2Y2R 在受损唾液腺恢复和再生中的作用。我们围绕几个具体目标组织了这些假设。具体目标 1 将鉴定介导腺泡形成的 P2Y2R 信号通路。具体目标 2 将研究整合素/P2Y2R 相互作用在腺泡形成所需的细胞反应中的作用。具体目标 3 将确定 P2Y2R 与肌动蛋白细胞骨架的相互作用是否调节 Par-C10 单层中的紧密连接组织。该提案中的 3 个具体目标旨在确定 P2Y2R 上调和激活增强唾液腺再生的机制，以开发更好的疗法来修复受损的唾液腺。 公共健康相关性：干燥综合征等疾病以及头颈癌的 3 次放射治疗会损害唾液腺。我们的研究发现了细胞表面的一种受体，即 P2Y2 核苷酸受体 (P2Y2R)，它在患病或受损的唾液腺中表达上调。先前的研究表明，P2Y2R的激活调节介导细胞增殖、迁移和分化的信号通路，这有力地支持了以下假设：受损或患病唾液腺中P2Y2R的表达和激活可用于促进组织修复和再生。