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: 9918153
• 负责人: PHILIP A BEACHY
• 金额: $ 33.79万
• 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/9918153
• 关键词: Ablation; Address; 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; Epithelium; 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; 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; 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organ regeneration; postnatal; prevent; severe injury; smoothened signaling pathway; stem cells; taste system; unpublished works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.

项目摘要/摘要 味觉感觉是基本人类生存的关键组成部分，因为它构成了歧视的贡献 摄入的物质可以维持我们和其他对我们福祉有害的物质。即使在现代 时代，我们周围有安全且丰富的养分来源，口味感觉成为一种重要的临床 当它的损失通常与癌症治疗中使用的细胞毒性治疗相关的问题时，会导致不必要的 减轻体重和生活质量的显着降低。发生这个问题的有趣表现 在接受刺猬（HH）途径拮抗剂治疗的癌症患者中，他们经历了累积的口味丧失 随着时间的流逝，感觉到HH途径活动可能对维持味觉系统至关重要。一个 先维持味道的其他线索是140年来的观察，即手术神经原因 味蕾变性。最后，我们观察到味觉神经元及其投影显示脂质 - 改性的HH蛋白配体在其表面上由Sonic Hedgehog（SHH）编码。这些观察结果 导致该提案中介绍的中心假设：神经元HH信号诱导并指定 从舌上皮的茎或祖细胞形成的从头味道受体细胞（TRC）的位置。 我们的提案解决了TRC替换以抵消普通稳态期间TRC流动率，以及 当化学疗法或HH途径造成接近完全损失时，需要批发再生 对抗。该假设也代表了一种新的生物学原理，即精确局部递送 远处神经元的过程的有效感应信号（HH）可以维持产后组织模式 （维持）或在重伤后从头形成（再生）期间施加正确的模式。到 确定神经元SHH信号如何支持TRC维护（AIM 1），我们建议确定关键 允许表达SHH神经元诱导TRC的功能，确定的时间特征 SHH信号的神经元提供的要求，并确定上皮的潜在贡献 SHH信号至TRC维护。要了解再生（AIM 2），我们将使用HH途径治疗小鼠 在消融TRC中特别有效的拮抗剂，然后在恢复期间跟踪TRC再生 确定刺猬途径活动是否限制，确定SHH信号的细胞表示， 并确定可能导致再生的其他提示。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（AIM 3）传递 已知在其他环境中释放HH蛋白的其他因素。我们研究的结果将扩大我们的 对味觉器官稳态和感觉器官再生的生物学理解，但也 应该有助于提高我们防止味觉丧失或促进其在细胞毒性患者中恢复的能力 癌症治疗。