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salivary cell; side effect; smoothened signaling pathway; therapeutic target; tissue repair; transcriptomics; tumor; unpublished works

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.

项目概要/摘要 流涎是一种重要的生理活动，有助于消化、保持口腔健康并支持诸如 由于年龄、疾病等导致言语、吞咽和味觉功能障碍。 干燥综合征和头颈癌放射治疗会导致永久性的放射治疗。 唾液腺受损，凸显其再生能力差是恢复的潜在障碍。 流涎可能是一种损害，特别是在放射治疗期间，不仅对产生唾液的人造成损害 事实上，上皮细胞也支持间充质细胞的保存或恢复。 细胞功能可能构成理想的治疗靶点，因为优化的间充质微环境可能 增强残留唾液腺上皮细胞及其祖细胞的功能和再生能力。 了解间充质细胞在稳态过程中如何发挥作用以及如何促进损伤后的再生 因此可能提供一种新的方法来激活保护唾液腺并增强其修复的机制。 在许多器官中，间充质表达信号，为上皮细胞提供再生反馈 在稳态和损伤修复过程中，刺猬 (Hh) 蛋白信号的表达可诱导 利用小鼠遗传模型、细胞谱系追踪和单细胞转录组学，我们得到了 发现沙漠刺猬 (DHH) 是三种哺乳动物 Hh 家族成员中研究最少的 成人主要唾液腺中的上皮间充质反馈（EMF）回路，以及该回路的活动 重要的是，该电路对于唾液腺的维持和辐射损伤后的再生至关重要。 唾液腺上皮细胞中的 DHH 表达对于再生至关重要，我们的研究结果还强调 间充质对此信号的反应对于执行再生程序起着至关重要的作用。 在这里，我们建议通过以下方式阐明 Hh 信号在唾液腺稳态和再生中的作用 在单细胞水平表征 EMF 回路活动的转录组和表观遗传后果，以及 评估人类唾液腺中 DHH 驱动的 EMF 电路的保护情况，目的是操纵它。 Hh 通路活性可防止辐射损伤或增强组织修复，我们开发了 针对 Hh 受体 Patched1 的构象特异性纳米抗体，可激活 Hh 通路反应。 纳米抗体可以靶向特定的细胞和组织类型，从而减轻潜在的不利影响 通过这种药物，我们将测试精确的、组织靶向激活的可能性。 Hh通路的研究可以有效增强唾液腺保护的内源性修复机制 因头颈癌治疗中的辐射造成的损伤和恢复后的恢复。