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salivary cell; side effect; smoothened signaling pathway; therapeutic target; tissue repair; transcriptomics; tumor; unpublished works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

项目总结/摘要 唾液分泌是一种重要的生理活动，有助于消化，保持口腔健康，并支持功能， 如言语、吞咽和味觉。唾液腺功能障碍是由衰老、疾病， 干燥综合征和头颈部癌症的放射治疗。治疗性照射导致永久性 唾液腺受损，突出了他们的再生能力差。一个潜在的障碍，以恢复 唾液分泌可能是损害，特别是在放射治疗期间，不仅对唾液产生造成损害 上皮细胞，而且支持间充质细胞。事实上，间充质细胞的保存或恢复 细胞功能可以构成理想的治疗靶点，因为优化的间充质微环境可以 增强残留唾液腺上皮细胞及其祖细胞的功能和再生能力。 了解间充质细胞在体内平衡过程中如何发挥作用，并有助于损伤后的再生 因此，可能提供一种新的方法来激活机制，保护唾液腺，并加强其修复。 在许多器官中，间充质表达的信号为上皮细胞提供再生反馈， 在体内平衡和损伤修复过程中，通过表达Hedgehog（Hh）蛋白信号诱导损伤修复。 上皮使用小鼠遗传模型，细胞谱系追踪和单细胞转录组学，我们有 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， 一个上皮间质反馈（EMF）电路在主要的成人唾液腺，这一活动， 在放射性损伤后，唾液腺的维持和再生中起着关键作用。重要的是，虽然 DHH在唾液腺上皮细胞中的表达对于再生是必不可少的，我们的研究结果也强调了 间充质对该信号的反应对于执行再生程序至关重要。 在这里，我们建议阐明Hh信号在唾液腺稳态和再生中的作用， 在单细胞水平上表征EMF电路活动的转录组学和表观遗传学后果，以及 评估DHH驱动的EMF电路在人类唾液腺中的保守性。目的是操纵 Hh通路活性的保护或增强组织修复后的辐射损伤，我们已经开发 针对Hh受体Patched 1的构象特异性纳米抗体，其激活Hh通路反应。这 纳米抗体可以靶向特定的细胞和组织类型，从而减轻由细胞和组织引起的潜在不良反应。 系统性Hh通路激活。有了这种药物，我们将测试精确的，组织靶向激活 Hh通路的激活能有效增强内源性修复机制， 放射损伤后的恢复，如头颈癌治疗中的放射损伤。