Taste and Cyclophosphamide in Mice

小鼠的味觉和环磷酰胺

基本信息

批准号：
8716727
负责人：
Eugene R Delay
金额：
$ 19.06万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-10 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716727
关键词：
Adult Adverse drug effect Adverse effects Affect Aftercare Ageusia Alkylating Agents Altered Taste Amifostine Amplifiers Antioxidants Behavioral Behavioral Assay Biological Bromodeoxyuridine Cancer Patient Cancerous Cell Cycle Cell Death Cells Cellular Assay Cyclophosphamide DNA DNA Damage Data Dietary intake Discrimination Dose Dysgeusia Eating Epithelium Esthesia Evaluation Reports Exposure to Food Aversion Foundations Future Health Homeostasis Human Injection of therapeutic agent Injury Knowledge Label Lead Learning Light Link Longevity Malignant Neoplasms Malnutrition Mitosis Mitotic Activity Modeling Molecular Mus Natural regeneration Nausea Normal Cell Patients Performance Pharmaceutical Preparations Population Process Property Quality of life Radiation therapy Radiosurgery Reaction Recovery Research S Phase Salivary Sensory Sodium Chloride Stem cells System Taste Buds Taste Perception Taste Threshold Testing Therapeutic Time Tissues base cancer cell cancer therapy cell type chemotherapy food consumption insight irradiation killings mortality novel prevent progenitor public health relevance repaired self-renewal sweet taste perception theories

项目摘要

DESCRIPTION (provided by applicant): Cyclophosphamide (CYP), widely used to treat cancer, will serve as a prototypical agent to study novel questions about how chemotherapy drugs disrupt taste, how cell populations within taste buds are renewed, and how we might protect these cells from the effects of chemotherapy drugs. Taste loss caused by chemotherapy frequently reduces food intake and results in malnutrition, lower quality of life, poorer recovery, and increased mortality. Prior research has focused mostly on how nausea and other side effects of these drugs form conditioned food aversions that reduce food consumption, or how these drugs disrupt salivary function. However, no one has asked how these drugs affect taste epithilium. CYP damages DNA during mitosis and thus targets cells engaged in high rates of mitosis such as cancer or adult progenitor cells of tissues with high rates of self-renewal. A noncancerous cell attacked by CYP is arrested in its cell cycle until its DNA is repaired, or the cell dies. In behavioral studies, one dose of CYP disrupted the ability of mice to discriminate between two similar tastes for up to 5 days post injection and again at 8-12 days post injection. Taste sensory cells have life spans of 8-12 days. When they die, they are replaced by cells derived from progenitor cells around the base of taste buds. Our initial findings suggest CYP kills or damages progenitor cells in taste epithelium and when surviving taste cells die 8-12 days later, there are insufficient replacement cells to maintain normal taste functions until the cell-renewal cycle is restarted. The proposed research has 3 Specific Aims to test our hypothesis that CYP induces cell death in taste buds and arrests mitotic activity of progenitor cells that normally replace taste sensory cells. Both effects disrupt taste functions but at different times after drug treatment. Aim 1 will assess the extent to which CYP alters taste functions of mice by testing their sensitivity and taste acuity for sweet, sour, bitter, and salt. Aim 2 will determine f CYP disrupts taste by killing taste cells and stopping the taste cell replacement cycle. Other cell markers will be used to determine when progenitor cells restart their cell cycles to generate replacement taste cells, and when specific taste cell types become functional. Aim 3 will test if amifostine can prevent taste loss and explore how it prevents taste cell death induced by CYP. Although this research is focused on chemotherapy drugs and taste, it uses a novel combination of behavioral and cellular assays that capitalize on the short life span of taste cells to study ho taste buds are repopulated, normally and after injury. This research will lay the foundation for future studies that more closely examine mechanisms underlying the effects of chemotherapy drugs, the processes underlying taste cell renewal, and possible mechanisms that can protect taste cells from the deleterious effects of cancer treatments, a significant health issue associated with the treatment of cancer. More broadly, this model can be used to study other forms of injury such as irradiation and is applicable for studying other tissues with rapid cell turnover.

描述（由申请人提供）：环磷酰胺（CYP）广泛用于治疗癌症，将作为原型剂来研究化疗药物如何破坏味觉、味蕾内的细胞群如何更新以及我们如何保护这些新问题。细胞免受化疗药物的影响。化疗引起的味觉丧失常常会减少食物摄入量，导致营养不良、生活质量下降、恢复较差、并增加死亡率。先前的研究主要集中在这些药物的恶心和其他副作用如何形成条件性食物厌恶，从而减少食物消耗，或者这些药物如何破坏唾液功能。然而，没有人询问这些药物如何影响味觉上皮细胞。 CYP 在有丝分裂过程中损伤 DNA，从而靶向参与高有丝分裂率的细胞，例如癌症或具有高自我更新率的组织的成体祖细胞。受到 CYP 攻击的非癌细胞会在其细胞周期中停滞，直到其 DNA 被修复或细胞死亡。在行为研究中，一剂 CYP 会在注射后长达 5 天和注射后 8-12 天再次破坏小鼠区分两种相似味道的能力。味觉细胞的寿命为8-12天。当它们死亡时，它们会被来自味蕾基部周围祖细胞的细胞所取代。我们的初步研究结果表明，CYP 会杀死或损害味觉上皮中的祖细胞，当存活的味觉细胞在 8-12 天后死亡时，没有足够的替代细胞来维持正常的味觉功能，直到细胞更新周期重新开始。拟议的研究有 3 个具体目标来检验我们的假设，即 CYP 诱导味蕾细胞死亡并阻止通常取代味觉感觉细胞的祖细胞的有丝分裂活性。这两种作用都会扰乱味觉功能，但在药物治疗后的不同时间发生。目标 1 将通过测试小鼠对甜、酸、苦和盐的敏感性和味觉敏锐度来评估 CYP 改变小鼠味觉功能的程度。目标 2 将确定 f CYP 通过杀死味觉细胞并停止味觉细胞更替周期来破坏味觉。其他细胞标记将用于确定祖细胞何时重新启动其细胞周期以产生替代味觉细胞，以及特定味觉细胞类型何时变得有功能。目标 3 将测试氨磷汀是否可以防止味觉丧失，并探索它如何防止 CYP 诱导的味觉细胞死亡。尽管这项研究的重点是化疗药物和味觉，但它使用了行为和细胞测定的新颖组合，利用味觉细胞的短暂寿命来研究味蕾在正常情况下和受伤后的再生情况。这项研究将为未来的研究奠定基础，更仔细地研究化疗药物作用的机制、味觉细胞更新的过程，以及保护味觉细胞免受癌症治疗有害影响的可能机制，癌症治疗是与癌症相关的一个重大健康问题。癌症的治疗。更广泛地说，该模型可用于研究其他形式的损伤，例如辐射，并且适用于研究细胞快速更新的其他组织。