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.

糖尿病前与乳腺癌风险增加有关。最近的研究已经认识到 以早期限制喂养（TRF）的形式进行间歇性禁食，避免了昼夜节律的同步 提高胰岛素抵抗。 TRF是一种饮食模式，可以通过协调来延长过夜禁食时间 摄入浅黑色昼夜节律的热量摄入量。长时间的夜间禁食时间可能与 乳腺癌和复发风险降低。长时间禁食的基本机械方面 尚不清楚与乳腺癌风险的持续时间和关系。 晚期糖基化最终产物（年龄）是反应性代谢产物，随着年龄的增长，它们会积聚在组织中。 现在，作为现代饮食的一部分，我们消耗了大量的年龄。年龄的致病作用 通过异常激活压力反应，导致胰岛素抵抗，糖尿病和癌症 途径。我们动物研究的高影响发现是饮食年龄诱导的乳腺肿瘤增加 增长受TRF的限制。饮食年龄介导的乳腺肿瘤生长增加取决于 年龄（愤怒）的跨膜受体的基质表达。可溶性愤怒（Srage）是一个广义的术语 用于定义循环中发现的各种截短的全长愤怒形式。它包含一个 致癌全怒的肿瘤抑制变体，被认为是在循环中被认为是隔离的年龄 充当诱饵受体。伴随TRF介导的饮食年龄诱导肿瘤生长的降低 SRAGE的显着增加。 我们假设TRF诱导的SRAGE增加可能代表通过减少的癌症风险改变 糖尿病前患者的年龄驾驶毒性。这项研究的目的是评估TRF对 乳腺癌风险较高的女性年龄驾驶毒性，并探索TRF的机械意义 饮食时代小鼠肿瘤模型中诱导的SRAGE。我们提出了两个具体目标。进行飞行员 旨在测量TRF对年龄段毒性的影响的随机对照试验（RCT） 绝经后妇女患有糖尿病前（SA1），并检查Srage上调的机制 对TRF体内的响应（SA2）。 必须识别疾病危险因素，以修改旨在降低乳腺癌风险的疗法 在弱势群体中。在糖尿病和乳腺癌中，SRAGE已被确定为临床上的重要性。作为 糖尿病的流行不断扩大，增加了乳腺癌高风险的女性人数， 识别SRAGE的机制和类型对TRF的响应增加将为较大的平台提供一个平台 干预研究。此类研究将旨在进一步定义针对环境的潜力 通过禁食为预防癌症的策略。