Hedgehog signaling in taste cell maintenance and regeneration

味觉细胞维持和再生中的刺猬信号传导

• 批准号: 10394796
• 负责人: PHILIP A BEACHY
• 金额: $ 34.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394796
• 关键词: Ablation; Address; Ageusia; Agonist; Back; Basal cell carcinoma; Biological; Body Weight decreased; Cancer Patient; Cell Maintenance; Cells; Cessation of life; Characteristics; Chemotherapy-Oncologic Procedure; Clinical; Cues; Cytotoxic Chemotherapy; Denervation; Desire for food; Development; Discrimination; Distant; Epithelial; Erinaceidae; Esthesia; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Ganglia; Generations; Genetic; Goals; Homeostasis; Human; In Vitro; Ingestion; Injury; Investigation; Lead; Ligands; Lipids; Location; Maintenance; Mediating; Methods; Modernization; Mus; Natural regeneration; Neurons; Nutrient; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Pattern; Personal Satisfaction; Pharmacology; Play; Positioning Attribute; Process; Property; Proteins; Quality of life; Receptor Cell; Recovery; Regenerative research; Reporting; Role; SHH gene; Sense Organs; Sensory; Sensory Process; Signal Induction; Signal Transduction; Signaling Protein; Source; Specific qualifier value; Surface; Taste Buds; Taste Perception; Testing; Time; Tissues; antagonist; base; cancer therapy; cell injury; cell regeneration; chemotherapy; cytotoxic; experience; experimental study; improved; neurotransmission; organ regeneration; postnatal; prevent; severe injury; smoothened signaling pathway; stem cells; taste system; unpublished works

PROJECT SUMMARY/ABSTRACT Taste sensation is a critical component of basic human survival, as it contributes centrally to the discrimination of substances whose ingestion sustains us and others that are detrimental to our well-being. Even in modern times, with safe and abundant sources of nutrients all around us, taste sensation becomes a significant clinical issue when its loss, often associated with the cytotoxic treatments employed in cancer therapy, causes unwanted weight reduction and a significant decrement in quality of life. An intriguing manifestation of this problem occurs in cancer patients treated with a Hedgehog (Hh) pathway antagonist, who experience cumulative loss of taste sensation over time, suggesting that Hh pathway activity may play a critical in maintaining the taste system. An additional clue to the basis of taste maintenance is the 140 year-old observation that surgical denervation causes taste bud degeneration. Finally, we observe that gustatory neurons and their projections display the lipid- modified Hh protein ligand encoded by Sonic hedgehog (Shh) on their surface. These observations together lead to the central hypothesis addressed in this proposal: that a neuronal Hh signal induces and specifies the position of de novo taste receptor cell (TRC) formation from stem or progenitor cells of the lingual epithelium. Our proposal addresses TRC replacement to offset TRC turnover during ordinary homeostasis, as well as the wholesale regeneration required when near-complete loss is inflicted by chemotherapy or Hh pathway antagonism. This hypothesis also represents a new biological principle, namely, that precisely localized delivery of a potent inductive signal (Hh) by processes from distant neurons can sustain postnatal tissue pattern (maintenance) or impose correct pattern during de novo organ formation after severe injury (regeneration). To determine how neuronal Shh signaling supports TRC maintenance (Aim 1), we propose to identify the critical features that allow Shh-expressing neurons to induce TRCs de novo, determine the temporal characteristics of the requirement for neuronal provision of the Shh signal, and determine the potential contribution of epithelial Shh signal to TRC maintenance. To understand regeneration (Aim 2) we will treat mice with a Hh pathway antagonist that is particularly efficient in ablating TRCs, then track TRC regeneration during a recovery period to determine whether Hedgehog pathway activity is limiting, determine the cellular presentation of the Shh signal, and identify other cues that may contribute to regeneration. Finally, we will determine the mechanism of Shh delivery via neuronal processes (Aim 3) by using specially marked Shh protein and testing the contributions of other factors known to function in release of Hh protein in other settings. The results of our study will expand our biological understanding of taste organ homeostasis and of sensory organ regeneration generally, but also should help improve our ability to prevent loss of taste or facilitate its recovery in patients undergoing cytotoxic cancer therapy.

项目概要/摘要 味觉是人类基本生存的重要组成部分，因为它对辨别能力有重要影响 摄入对我们和其他人的健康有害的物质。即使在现代 时代，我们周围有安全和丰富的营养来源，味觉成为一个重要的临床 当它的丢失（通常与癌症治疗中使用的细胞毒性治疗相关）导致不必要的问题时，就会出现问题 体重减轻，生活质量显着下降。这个问题出现了一个有趣的表现 在接受 Hedgehog (Hh) 通路拮抗剂治疗的癌症患者中，他们经历了味觉的累积丧失 随着时间的推移，感觉会发生变化，这表明 Hh 通路活性可能在维持味觉系统方面发挥着关键作用。一个 味觉维持基础的另一个线索是 140 年前手术去神经术引起的观察 味蕾退化。最后，我们观察到味觉神经元及其投射显示脂质 其表面由音速刺猬 (Shh) 编码的修饰 Hh 蛋白配体。这些观察结果加在一起 引出了本提案中提出的中心假设：神经元 Hh 信号诱导并指定 舌上皮干细胞或祖细胞从头形成味觉受体细胞 (TRC) 的位置。 我们的提案涉及 TRC 替换，以抵消正常稳态期间的 TRC 周转率，以及 当化疗或 Hh 途径导致几乎完全丧失时需要大规模再生 对抗。这一假说还代表了一个新的生物学原理，即精确定位递送 来自远处神经元过程的有效感应信号（Hh）可以维持产后组织模式 （维护）或在严重损伤后从头器官形成过程中施加正确的模式（再生）。到 为了确定神经元 Shh 信号如何支持 TRC 维持（目标 1），我们建议确定关键的 允许表达 Shh 的神经元从头诱导 TRC 的特征，决定了 神经元提供Shh信号的要求，并确定上皮细胞的潜在贡献 向 TR​​C 维护发出嘘信号。为了了解再生（目标 2），我们将用 Hh 途径治疗小鼠 在消除 TRC 方面特别有效的拮抗剂，然后在恢复期间跟踪 TRC 再生，以 确定 Hedgehog 通路活性是否受到限制，确定 Shh 信号的细胞表达， 并确定可能有助于再生的其他线索。最后，我们将确定Shh的机制 通过使用特殊标记的 Shh 蛋白并测试的贡献，通过神经元过程进行传递（目标 3） 已知在其他环境中释放 Hh 蛋白的其他因素。我们的研究结果将扩展我们的 对味觉器官稳态和感觉器官再生的生物学理解，而且 应该有助于提高我们防止接受细胞毒性治疗的患者味觉丧失或促进其恢复的能力 癌症治疗。