权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10420976
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
项目类别：
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/10420976
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 Epithelial Cells 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 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 Pharmacology Physiological Play Process Radiation Radiation Injuries Radiation therapy Recovery Regenerative capacity Research Residual state Resolution Risk Role Saliva Salivary Gland Tissue Salivary Glands Signal Transduction Signaling Protein Sjogren&apos s Syndrome Speech Submandibular gland Sum Supporting Cell Taste Perception Testing Therapeutic Tissues Well in self Work Xerostomia cancer therapy cell type genome-wide in vivo injury and repair irradiation macrophage mouse genetics mouse model nanobodies nerve supply novel strategies 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secretion salivary cell side effect smoothened signaling pathway therapeutic target tissue repair transcriptomics tumor unpublished works

项目摘要

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/文摘