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: 9066827
• 负责人: PHILIP A BEACHY
• 金额: $ 21.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066827
• 关键词: Ablation; Acute; Address; Adult; Afferent Neurons; Agonist; Basal Cell; Basal cell carcinoma; Biological; Body Weight decreased; Cancer Patient; Cell Maintenance; Cell Separation; Cells; Cessation of life; Clinical; Denervation; Development; Discrimination; Dysgeusia; Environment; Epithelial Cells; Epithelium; Erinaceidae; Esthesia; Exposure to; FDA approved; Gene Expression Profiling; Generations; Genetic; Goals; Health; Homeostasis; Housing; Human; In Vitro; Ingestion; Injury; Investigation; Ligands; Lipids; Location; Maintenance; Malignant Neoplasms; Memory; Methods; Modality; Mus; Natural regeneration; Nature; Neurons; Nutrient; Operative Surgical Procedures; Organ; Organoids; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Play; Poison; Process; Proteins; Quality of life; Radiation therapy; Receptor Cell; Recovery; Reporting; Rest; Role; SHH gene; Sensory; Shapes; Signal Transduction; Signaling Protein; Source; Specific qualifier value; Staging; Structure; Surface; System; Taste Buds; Taste Perception; Testing; Therapeutic Agents; Time; Tongue; Withdrawal; Work; base; cancer therapy; cytotoxic; genetic approach; improved; in vitro testing; in vivo; medulloblastoma; nerve supply; prevent; regenerative; response; sensory input; smoothened signaling pathway; taste system; tool

 DESCRIPTION (provided by applicant): The sensation of taste contributes centrally to discrimination of substances whose ingestion sustains us and others that are detrimental to our well-being. Taste sensation is thus a critical component of basic human survival. 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 neuronal damage or the cytotoxic treatments and radiation employed in cancer therapy, causes unwanted weight reduction and a significant decrement in quality of life. A particularly acute manifestation of thi problem occurs in cancer patients treated with a Hedgehog (Hh) pathway antagonist who are forced or choose to discontinue therapy due to loss of taste sensation, a specific biological effect caused by this class of mechanism-based cancer therapeutic agent. Our proposal focuses on the role of Hh signaling in maintenance and regeneration of taste receptor cells (TRCs), which are housed within cup-shaped structures formed by invagination of the lingual epithelium (taste buds). We plan to determine the cellular source of the Hedgehog signal and the nature of its effects and, of particular significance; we will address the role of Shh ligand provided by sensory neurons that innervate TRCs. The Hh signal produced by these neurons may represent a cellular memory that specifies TRC regeneration within taste buds, as opposed to other parts of the lingual epithelium. Such memory may serve as a fundamental mechanism that coordinates the location of regenerative signaling with the presence of innervation that is able to receive and process sensory input, and may be relevant to the homeostasis and regeneration of other sensory organs. In addition, because Hh pathway manipulation provides a powerful tool to cause loss or gain of TRCs, we will be able to compare degenerating and regenerating states to identify other secreted factors that may play a role. These advances will expand our biological understanding of homeostasis and regeneration of sensory organs generally, and will improve our ability to prevent loss of taste or facilitate its recovery in patints undergoing cancer therapy. Our experimental aims are: Aim 1: Determine the cellular source of the Hh signal and its role in maintenance of TRCs. Conditional genetic approaches will be used to determine how Shh signaling functions in TRC maintenance. Aim 2: Define the role of Shh from gustatory sensory neurons in regeneration of TRCs. Surgical denervation, conditional genetic and pharmacological approaches, and organoid culture will be used to assess the role of neuronal Shh in TRC regeneration. Aim 3. Identify Hh-dependent factors required for maintenance and regeneration of TRCs. Gene expression profiling of FACS-sorted cells will be used to identify Hh-dependent factors that contribute to TRC maintenance and regeneration. Candidates will be tested in vitro in organoid culture and in vivo.

 描述（由申请人提供）：味觉主要有助于区分摄入维持我们的物质和其他对我们健康有害的物质。因此，味觉是人类基本生存的关键组成部分。即使在现代，我们周围有安全和丰富的营养来源，味觉也成为一个重要的临床问题，因为味觉的丧失通常与神经元损伤或癌症治疗中使用的细胞毒性治疗和放射有关，导致不必要的体重减轻和生活质量的显著下降。该问题的特别急性表现发生在用Hedgehog（Hh）途径拮抗剂治疗的癌症患者中，所述癌症患者由于味觉丧失而被迫或选择停止治疗，味觉丧失是由这类基于机制的癌症治疗剂引起的特定生物学效应。 我们的建议集中在Hh信号在味觉受体细胞（TRC）的维持和再生中的作用，TRC被安置在舌上皮（味蕾）内陷形成的杯状结构内。我们计划确定刺猬信号的细胞来源及其影响的性质，特别重要的是，我们将讨论由支配TRCs的感觉神经元提供的Shh配体的作用。由这些神经元产生的Hh信号可能代表细胞记忆，其指定味蕾内的TRC再生，而不是舌上皮的其他部分。这种记忆可以作为一种基本机制，协调再生信号的位置与能够接收和处理感觉输入的神经支配的存在，并且可能与其他感觉器官的稳态和再生有关。此外，由于Hh通路操纵提供了一个强大的工具，导致TRC的损失或增益，我们将能够比较退化和再生状态，以确定其他分泌因子可能发挥作用。这些进展将扩大我们对感觉器官的体内平衡和再生的生物学理解，并将提高我们预防味觉丧失或促进癌症治疗患者味觉恢复的能力。我们的实验目的是：目的1：确定Hh信号的细胞来源及其在TRC维持中的作用。条件遗传学方法将用于确定Shh信号在TRC维持中的功能。目的2：明确味觉感觉神经元分泌的Shh在TRCs再生中的作用。手术去神经，条件遗传和药理学方法，和类器官培养将用于评估神经元Shh在TRC再生中的作用。目标3.确定TRC维持和再生所需的Hh依赖因素。FACS分选细胞的基因表达谱将用于鉴定有助于TRC维持和再生的Hh依赖性因子。候选物将在类器官培养物和体内进行体外测试。