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）：味觉对于区分我们和其他对我们的健康造成困扰的物质至关重要，因此，即使在现代，味觉也是人类基本生存的重要组成部分。味觉是我们周围安全和丰富的营养来源，当味觉丧失（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）导致体重减轻和生活质量显着下降时，味觉就成为一个重要的临床问题。一个特别这个问题的急性表现发生在接受 Hedgehog (Hh) 途径拮抗剂治疗的癌症患者中，他们由于味觉丧失而被迫或选择停止治疗，味觉丧失是此类基于机制的癌症治疗剂引起的特定生物效应。该提案的重点是 Hh 信号在味觉受体细胞 (TRC) 的维持和再生中的作用，味觉受体细胞位于由舌上皮（味蕾）内陷形成的杯形结构内。 Hedgehog 信号的来源及其作用的性质，特别重要的是，我们将讨论由支配 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 TRC 再生的细胞记忆。与舌上皮的其他部分相反，这种记忆可能作为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基本机制。此外，由于 Hh 通路操纵提供了导致 TRC 丢失或增加的强大工具，因此我们将能够比较退化和再生状态，以确定可能发挥作用的其他分泌因子。这些进展将扩大我们对感觉器官稳态和再生的生物学理解，并将提高我们防止接受癌症治疗的患者味觉丧失或促进味觉恢复的能力。我们的实验目标是： 目标 1：确定 Hh 信号的细胞来源及其在 TRC 维持中的作用将用于确定 Shh 信号在 TRC 维持中的作用 目标 2：定义味觉感觉神经元的 Shh 在 TRC 再生中的作用。去神经、条件遗传和药理学方法以及类器官培养将用于评估神经 Shh 在 TRC 再生中的作用。目标 3. 确定维持所需的 Hh 依赖性因子。 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。候选者将在类器官培养物和体内进行体外测试。

项目成果

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration.

Hedgehog 的神经元传递指导味觉器官再生的空间模式。

• 发表时间: 2018-01-09
• 影响因子: 11.1
• 作者: Lu, Wan;Mann, Randall K;Nguyen, Allison;Bi, Tingting;Silverstein, Ma;Tang, Jean Y;Chen, Xiaoke;Beachy, Philip A
• 通讯作者: Beachy, Philip A