Taste and Cyclophosphamide in Mice

小鼠的味觉和环磷酰胺

基本信息

批准号：
8578205
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/8578205
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）：广泛用于治疗癌症的环磷酰胺（CYP）将用作典型的剂，以研究有关化学疗法药物如何破坏味道，味蕾中的细胞种群如何更新以及我们如何保护这些细胞免受化学疗法药物的影响。化学疗法引起的味觉丧失经常减少食物摄入量并导致营养不良，降低生活质量，恢复较差，并增加死亡率。先前的研究主要集中于这些药物的恶心和其他副作用如何形成有条件的食物厌恶，从而减少食物的消耗，或者这些药物如何破坏唾液功能。但是，没有人问这些药物如何影响味道上皮。 CYP在有丝分裂过程中损害DNA，因此靶向具有高丝分裂率的细胞，例如癌症或成年祖细胞，其自我更新率很高。由CYP攻击的非癌细胞在其细胞周期中被捕，直到修复其DNA或细胞死亡。在行为研究中，一剂CYP破坏了小鼠在注射后长达5天的两种类似口味的能力，并在注射后8-12天再次区分。口味感官细胞的寿命为8-12天。当它们死亡时，它们被源自味蕾底部周围祖细胞的细胞所取代。我们的最初发现表明，CYP会杀死或损坏味觉上皮中的祖细胞，而幸存的味觉细胞在8-12天后死亡时，替代细胞不足以维持正常的味觉功能，直到重新启动细胞续订循环为止。拟议的研究具有3个特定的目的，目的是检验我们的假设，即CYP诱导味蕾中的细胞死亡，并阻止通常取代味觉感觉细胞的祖细胞的有丝分裂活性。两种影响都破坏了口味功能，但在药物治疗后的不同时间。 AIM 1将通过测试对甜，酸，苦味和盐的敏感性和敏锐度来评估CYP在多大程度上改变小鼠的口味功能。 AIM 2将通过杀死味觉细胞并停止味觉细胞替代周期来确定F CYP的味道。其他单元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，以及何时特定的味觉细胞类型起作用。 AIM 3将测试Amifostine是否可以防止口味丧失，并探索其如何防止CYP诱导的味觉细胞死亡。尽管这项研究的重点是化学疗法药物和味道，但它使用了行为和细胞测定法的新型组合，这些结合利用了味道细胞的短寿命来研究Ho味芽，通常是在受伤后和受伤后的。这项研究将为未来的研究奠定基础，该研究更加仔细地研究化学疗法药物的作用，味道细胞更新的过程以及可以保护味觉细胞免受癌症治疗的有害影响的可能机制，这是与癌症治疗相关的重要健康问题。更广泛地说，该模型可用于研究其他形式的损伤，例如辐射，适用于研究其他细胞更新的其他组织。