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（由适用提供）：味道的感觉在歧视我们的摄入习惯和其他对我们幸福感的物质的歧视中心。因此，味觉是基本人类生存的关键组成部分。即使在现代，当我们周围的营养源安全和丰富的来源中，当通常与神经元损伤或细胞毒性治疗相关的损失或在癌症治疗中采用辐射的损失时，口味感觉也成为一个重大的临床问题，会导致减轻不良的体重减轻并减少生活质量。在用刺猬（HH）途径拮抗剂治疗的癌症患者中，这种问题的特别急性表现出现，他们被迫或选择因味觉感觉丧失而停止治疗，这是由这种基于机械机制的癌症治疗剂引起的特定生物学作用。我们的建议着重于HH信号在维持和再生味觉受体细胞（TRC）中的作用，这些作用嵌入了由舌形上皮（味蕾）内陷形成的杯形结构中。我们计划确定刺猬信号的细胞来源及其作用的性质，并具有尤其重要。我们将解决神经TRC的感觉神经元提供的SHH配体的作用。这些神经元产生的HH信号可能代表了指定味蕾内TRC再生的细胞记忆，而不是舌上上皮的其他部分。这种记忆可能是一种基本机制，可以协调再生信号传导的位置与能够接收和处理感觉输入的神经的存在，并且可能与其他感觉器官的体内稳态和再生有关。此外，由于HH途径的操纵提供了导致TRC损失或增益的强大工具，因此我们将能够比较退化和再生状态，以识别可能发挥作用的其他分泌因素。这些进步将扩大我们对体内稳态和感觉器官再生的生物学理解，并提高我们防止味道丧失或对接受癌症治疗的模式的恢复的能力。我们的实验目的是：目标1：确定HH信号的细胞来源及其在维持TRC中的作用。条件遗传方法将用于确定SHH信号在TRC维持中的功能。 AIM 2：定义SHH来自味觉感觉神经元在TRC再生中的作用。手术神经保护，有条件的遗传和药物方法以及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依赖性因素。 FACS分类细胞的基因表达分析将用于鉴定有助于TRC维持和再生的HH依赖性因素。候选物将在器官培养和体内进行体外测试。