Taste and Cyclophosphamide in Mice

小鼠的味觉和环磷酰胺

• 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
• 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

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（Cyclophosphamide）将作为一种原型药物，研究有关化疗药物如何破坏味觉，味蕾内细胞群如何更新以及我们如何保护这些细胞免受化疗药物影响的新问题。化疗引起的味觉丧失经常减少食物摄入，导致营养不良，生活质量降低，恢复较差， 和死亡率的增加。之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减少食物消耗的条件性食物厌恶，或者这些药物如何破坏唾液功能。然而，没有人问这些药物如何影响味觉上皮。在有丝分裂过程中，DNA损伤，因此靶向参与高速率有丝分裂的细胞，如癌症或具有高速率自我更新的组织的成体祖细胞。一个非癌细胞被细菌攻击后，其细胞周期会被阻滞，直到其DNA被修复，或者细胞死亡。在行为学研究中，一个剂量的三聚氰胺在注射后5天内破坏了小鼠区分两种相似味道的能力，并在注射后8-12天再次破坏。味觉感觉细胞的寿命为8-12天。当它们死亡时，它们被味蕾基部周围的祖细胞衍生的细胞所取代。我们的初步研究结果表明，味觉上皮细胞中的祖细胞被杀死或损伤，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个具体目的来测试我们的假设，即唾液酸诱导味蕾细胞死亡，并阻止通常取代味觉细胞的祖细胞的有丝分裂活动。这两种作用都会破坏味觉功能，但在药物治疗后的不同时间。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甜味剂改变小鼠味觉功能的程度。目标2将确定氟通过杀死味觉细胞和停止味觉细胞替代周期来破坏味觉。其他细胞 标记物将用于确定祖细胞何时重新开始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。目的3将测试氨磷汀是否可以防止味觉丧失，并探索它如何防止味觉细胞死亡诱导的味觉。虽然这项研究主要集中在化疗药物和味觉上，但它使用了一种新颖的行为和细胞分析的组合，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重新繁殖情况。这项研究将为未来的研究奠定基础，更密切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，这是一个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，如辐射，并适用于研究其他组织与快速细胞更新。