The effects of time restricted feeding on AGE-RAGE signaling in women at high risk for breast cancer

限时喂养对乳腺癌高危女性 AGE-RAGE 信号的影响

• 批准号: 10625580
• 负责人: Victoria Jane Findlay
• 金额: $ 33.07万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625580
• 关键词: effects; time; restricted; feeding; AGE

Pre-diabetes is associated with increased breast cancer risk. Recent studies have recognized a role for intermittent fasting, in the form of early time restricted feeding (TRF), in avoiding circadian de-synchrony to improve insulin resistance. TRF is an eating pattern that prolongs the overnight fasting duration by coordinating caloric intake with light-dark circadian rhythm. Prolonged nighttime fasting duration may be associated with reduced breast cancer and recurrence risk. The underlying mechanistic aspects of prolonged overnight fasting duration and relationship to breast cancer risk is not yet known. Advanced glycation end products (AGEs) are reactive metabolites that accumulate in tissues as we grow older. We now consume copious amounts of AGEs as part of the modern diet. The pathogenic effects of AGEs contribute to insulin resistance, diabetes and cancer through the aberrant activation of stress response pathways. A high impact finding of our animal studies is that dietary-AGE induced increases in breast tumor growth are restricted by TRF. Dietary-AGE mediated increases in breast tumor growth were dependent upon the stromal expression of the transmembrane receptor for AGE (RAGE). Soluble RAGE (sRAGE) is a broad term used to define various truncated forms of full length RAGE that are found in the circulation. It encompasses a group of tumor suppressive variants of the oncogenic full RAGE, thought to sequester AGE in the circulation by acting as a decoy receptor. Accompanying the TRF mediated decreases in dietary-AGE induced tumor growth was a significant increase in sRAGE. We hypothesize that TRF induced increases in sRAGE may represent a cancer risk modification by reducing AGE-RAGE toxicity in patients with pre-diabetes. The objective of this study is to assess the impact of TRF on AGE-RAGE toxicity in women at higher risk of breast cancer, and explore the mechanistic implications of TRF induced sRAGE in dietary-AGE mouse tumor models. We propose two specific aims; To conduct a pilot Randomized Controlled Trial (RCT) designed to measure the effect of TRF on AGE-RAGE toxicity in postmenopausal women with pre-diabetes (SA1) and to examine the mechanism of sRAGE upregulation in response to TRF in vivo (SA2). It is essential to identify disease risk factors in order to modify therapies aimed at decreasing breast cancer risk in vulnerable populations. sRAGE has been identified as clinically important in diabetes and breast cancer. As the epidemic of diabetes continues to expand, increasing the number of women at high risk of breast cancer, identifying the mechanism and type of sRAGE increased in response to TRF will provide a platform for larger intervention studies. Such studies would be aimed at further defining the potential of targeting environmental AGE as a cancer prevention strategy through fasting.

糖尿病前期与乳腺癌风险增加有关。最近的研究已经认识到 间歇性禁食，以早期限制喂养（TRF）的形式，避免昼夜节律不同步， 改善胰岛素抵抗。TRF是一种饮食模式，通过协调 热量摄入与明暗昼夜节律。夜间禁食时间延长可能与 降低乳腺癌和复发风险。长期过夜禁食的潜在机制方面 持续时间和与乳腺癌风险的关系尚不清楚。 晚期糖基化终末产物（AGEs）是一种活性代谢产物，随着年龄的增长在组织中积累。 我们现在消耗大量的AGEs作为现代饮食的一部分。AGEs的致病作用 通过应激反应的异常激活导致胰岛素抵抗、糖尿病和癌症 途径。我们的动物研究的一个高影响力的发现是，饮食AGE诱导乳腺肿瘤的增加 增长受到扶轮基金会的限制。饮食-AGE介导的乳腺肿瘤生长的增加依赖于 AGE跨膜受体（AGE）的基质表达。可溶性淀粉（sodium）是一个广义的术语， 用于定义在循环中发现的各种截短形式的全长螺旋桨。它包括 一组肿瘤抑制性的致癌性全基因突变体，被认为是在循环中隔离AGE， 作为诱饵受体。伴随着TRF介导的饮食AGE诱导的肿瘤生长的减少 是一个显着的增加在south。 我们假设TRF诱导的sCRP增加可能代表了癌症风险的改变， 糖尿病前期患者中的AGE-R毒性。本研究的目的是评估扶轮基金会对 乳腺癌高危女性的AGE-resistance毒性，并探讨TRF的机制意义 在饮食-AGE小鼠肿瘤模型中诱导肿瘤。我们提出两个具体目标： 随机对照试验（RCT），旨在测量TRF对AGE-E2毒性的影响， 绝经后妇女糖尿病前期（SA 1），并检查sCRP上调的机制， 体内对TRF的反应（SA 2）。 识别疾病风险因素以改进旨在降低乳腺癌风险的治疗是至关重要的 在弱势群体中。已确定糖尿病和乳腺癌中的胰岛素具有临床重要性。作为 糖尿病的流行继续扩大，增加了患乳腺癌高风险的妇女人数， 确定响应扶轮基金会而增加的sweep的机制和类型将提供一个平台， 干预研究。这些研究的目的是进一步确定以环境为目标的可能性， AGE作为通过禁食的癌症预防策略。