Salivary gland response to Desert hedgehog signaling as an antidote to damage from therapeutic radiation

唾液腺对沙漠刺猬信号的反应作为治疗辐射损伤的解毒剂

• 批准号: 10592398
• 负责人: PHILIP A BEACHY
• 金额: $ 52.57万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592398
• 关键词: ATAC-seq; Ablation; Acinar Cell; Adult; Adverse effects; Aging; Antidotes; Artificial Saliva; Atrophic; Bladder; Cell Lineage; Cell physiology; Cell surface; Cells; Clinical; Data; Deglutition; Digestion; Disease; Engineering; Epigenetic Process; Epithelial Cells; Epithelium; Erinaceidae; Esthesia; Exposure to; Family member; Feedback; Functional disorder; Genetic; Genetic Models; Goals; Head and Neck Cancer; Homeostasis; Host Defense; Human; In Situ Hybridization; Injury; Intestines; Knowledge; Ligands; Macrophage; Maintenance; Major salivary gland structure; Mediating; Mesenchymal; Mesenchyme; Methods; Minor; Molecular; Molecular Conformation; Mus; Myoepithelial cell; Natural regeneration; Oral; Oral cavity; Oral health; Oral mucous membrane structure; Organ; Parotid Gland; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Process; Radiation; Radiation Injuries; Radiation therapy; Recovery; Regenerative capacity; Research; Residual state; Resolution; Risk; Role; Saliva; Salivary Gland Tissue; Salivary Glands; Signal Pathway; Signal Transduction; Signaling Protein; Sjogren' s Syndrome; Speech; Submandibular gland; Supporting Cell; Taste Perception; Testing; Therapeutic; Tissues; Well in self; Work; Xerostomia; cancer therapy; cell type; genome-wide; in vivo; injury and repair; irradiation; mouse genetics; mouse model; nanobodies; nerve supply; novel strategies; pharmacologic; preservation; progenitor; programs; radiation recovery; receptor; regenerative; repaired; response; restoration; saliva secretion; salivary cell; side effect; smoothened signaling pathway; therapeutic target; tissue repair; transcriptomics; tumor; unpublished works; ATAC-seq; Ablation; Acinar Cell; Adult; Adverse effects; Aging; Antidotes; Artificial Saliva; Atrophic; Bladder; Cell Lineage; Cell physiology; Cell surface; Cells; Clinical; Data; Deglutition; Digestion; Disease; Engineering; Epigenetic Process; Epithelial Cells; Epithelium; Erinaceidae; Esthesia; Exposure to; Family member; Feedback; Functional disorder; Genetic; Genetic Models; Goals; Head and Neck Cancer; Homeostasis; Host Defense; Human; In Situ Hybridization; Injury; Intestines; Knowledge; Ligands; Macrophage; Maintenance; Major salivary gland structure; Mediating; Mesenchymal; Mesenchyme; Methods; Minor; Molecular; Molecular Conformation; Mus; Myoepithelial cell; Natural regeneration; Oral; Oral cavity; Oral health; Oral mucous membrane structure; Organ; Parotid Gland; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Process; Radiation; Radiation Injuries; Radiation therapy; Recovery; Regenerative capacity; Research; Residual state; Resolution; Risk; Role; Saliva; Salivary Gland Tissue; Salivary Glands; Signal Pathway; Signal Transduction; Signaling Protein; Sjogren' s Syndrome; Speech; Submandibular gland; Supporting Cell; Taste Perception; Testing; Therapeutic; Tissues; Well in self; Work; Xerostomia; cancer therapy; cell type; genome-wide; in vivo; injury and repair; irradiation; mouse genetics; mouse model; nanobodies; nerve supply; novel strategies; pharmacologic; preservation; progenitor; programs; radiation recovery; receptor; regenerative; repaired; response; restoration; saliva secretion; salivary cell; side effect; smoothened signaling pathway; therapeutic target; tissue repair; transcriptomics; tumor; unpublished works

PROJECT SUMMARY/ABSTRACT Salivation is a critical physiological activity that aids digestion, maintains oral health, and supports functions such as speech, swallowing and taste sensation. Salivary gland dysfunction results from ageing, diseases such as Sjögren syndrome and from radiotherapy for head and neck cancers. Therapeutic irradiation causes permanent damage to salivary glands, highlighting their poor regenerative ability. One potential obstacle to recovery of salivation may be that damage, particularly during radiation therapy, is inflicted not only on saliva-generating epithelial cells but also on supporting mesenchymal cells. Indeed, preservation or restoration of mesenchymal cell function may constitute an ideal therapeutic target, as an optimized mesenchymal microenvironment may augment the function and regenerative capacity of residual salivary gland epithelial cells and their progenitors. A knowledge of how mesenchymal cells function during homeostasis and contribute to regeneration after injury thus may provide a new approach to activate mechanisms that protect salivary glands and enhance their repair. In many organs the mesenchymal expression of signals that provide regenerative feedback to the epithelium during homeostasis and injury repair is induced by expression of a Hedgehog (Hh) protein signal from the epithelium. Using mouse genetic models, cell lineage tracing, and single-cell transcriptomics, we have discovered that Desert hedgehog (DHH), the least studied of the three mammalian Hh family members, drives an epithelial-mesenchymal feedback (EMF) circuit in the major adult salivary glands, and that activity of this circuit is crucial for salivary gland maintenance and for regeneration after radiation injury. Importantly, although DHH expression in cells of the salivary gland epithelium is essential for regeneration, our findings also highlight a vital role for mesenchymal response to this signal for execution of the regenerative program. Here we propose to elucidate the role of Hh signaling in salivary gland homeostasis and regeneration by characterizing at a single cell level the transcriptomic and epigenetic consequences of EMF circuit activity, and to assess the conservation of DHH-driven EMF circuitry in human salivary glands. With the goal of manipulating Hh pathway activity for protection from or enhancement of tissue repair after radiation injury, we have developed a conformation-specific nanobody against the Hh receptor Patched1 that activates Hh pathway response. This nanobody can be targeted to specific cell and tissue types, thus mitigating potential adverse effects arising from systemic Hh pathway activation. With this agent, we will test the possibility that precise, tissue-targeted activation of the Hh pathway can effectively enhance endogenous reparative mechanisms for salivary gland protection from and restoration after injury from irradiation like that administered in head and neck cancer therapy.

项目摘要/摘要 唾液是一项关键的体育活动，可帮助消化，维持口腔健康并支持这样的功能 作为言语，吞咽和味觉。唾液腺功能障碍来自衰老，疾病，例如 Sjögren综合征和头颈癌的放疗。治疗辐射会导致永久性 对唾液场的损害，突出了它们的再生能力。恢复的潜在障碍 唾液可能是造成损害，特别是在放射治疗期间，不仅在生成唾液时会造成 上皮细胞，但也支持间质细胞。确实，保存或恢复间充质 细胞功能可能构成理想的治疗靶标，因为优化的间充质微环境可能 增强残留的唾液腺上皮细胞及其祖细胞的功能和再生能力。 了解Messectemal细胞在稳态期间的功能以及受伤后的再生的知识 这可能会提供一种新方法来激活保护唾液网格并增强其修复的机制。 在许多器官中 在体内稳态和损伤过程中，通过表达刺猬（HH）蛋白信号的诱导 上皮。使用小鼠遗传模型，细胞谱系跟踪和单细胞转录组学，我们有 发现沙漠刺猬（DHH）是三个哺乳动物HH家庭成员的最少研究 主要成人唾液腺中的上皮 - 间质反馈（EMF）电路，并且这种活性 电路对于唾液腺维持和辐射损伤后的再生至关重要。重要的是，虽然 唾液腺上皮细胞中的DHH表达对于再生至关重要，我们的发现也突出显示 间充质响应对该信号的至关重要的作用，用于执行再生程序。 在这里，我们建议阐明HH信号在唾液腺稳态中的作用，并通过 在单个细胞水平上表征EMF电路活性的转录组和表观遗传学后果，以及 评估人类唾液网格中DHH驱动的EMF电路的保护。以操纵为目标 HH途径活性，可保护辐射损伤后的组织修复或增强，我们已经发展 针对HH受体Patched1的特定会议特异性纳米病，可激活HH途径响应。这 纳米机构可以针对特定的细胞和组织类型，从而减轻 全身HH途径激活。使用该试剂，我们将测试精确，靶向组织的激活的可能性 HH途径可以有效地增强内源性修复机制，以保护唾液腺保护 受辐射后的恢复和恢复，例如在头颈癌治疗中给药。