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: 10304658
• 负责人: Victoria Jane Findlay
• 金额: $ 5.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2022-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304658
• 关键词: Address; Adherence; Adult; Advanced Glycosylation End Products; Affect; Animals; Blood Circulation; Breast Cancer Patient; Breast Cancer Risk Factor; Circadian Rhythms; Clinical; Consumption; Development; Diabetes Mellitus; Diet; Eating; Energy Intake; Epidemic; Fasting; Feces; Future; High Risk Woman; Human; Incidence; Individual; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intake; Intermittent fasting; Intervention; Intervention Studies; Lead; Length; Life Style; Light; Link; MMP9 gene; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Modeling; Modernization; Modification; Molecular; Mus; Oncogenic; Outcome; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pilot Projects; Plasma; Postmenopause; Prediabetes syndrome; Prevention strategy; Process; RNA Splicing; Randomized Controlled Trials; Regulation; Renal clearance function; Research; Risk; Risk Factors; Role; Serum; Signal Transduction; Time-restricted feeding; Tissues; Toxic effect; United States; Up-Regulation; Urine; Variant; Vulnerable Populations; Woman; biological adaptation to stress; cancer prevention; cancer recurrence; cancer risk; circadian; dietary; disorder risk; fasting glucose; high risk; high risk population; improved; improved outcome; in vivo; malignant breast neoplasm; mouse model; novel strategies; prevent; receptor; receptor for advanced glycation endproducts; response; soluble RAGE; treatment response; trial design; tumor; tumor growth

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，以早期限制进食（TRF）的形式，避免昼夜节律不同步 改善胰岛素抵抗。 TRF 是一种通过协调来延长隔夜禁食时间的饮食模式 热量摄入具有明暗昼夜节律。夜间禁食时间延长可能与 降低乳腺癌和复发风险。长时间隔夜禁食的潜在机制 持续时间以及与乳腺癌风险的关系尚不清楚。 晚期糖基化终末产物 (AGE) 是随着年龄的增长而在组织中积累的反应性代谢物。 作为现代饮食的一部分，我们现在摄入大量的 AGE。 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具有重大影响的发现是饮食中的 AGE 诱导乳腺肿瘤的增加 生长受到 TRF 的限制。饮食-AGE介导的乳腺肿瘤生长增加取决于 AGE 跨膜受体 (RAGE) 的基质表达。可溶性 RAGE (sRAGE) 是一个广义术语 用于定义流通中发现的全长 RAGE 的各种截断形式。它包括一个 一组致癌性完整 RAGE 的肿瘤抑制变体，被认为通过以下方式隔离循环中的 AGE： 充当诱饵受体。伴随 TRF 介导的饮食-AGE 诱导的肿瘤生长的减少 sRAGE显着增加。 我们假设 TRF 诱导的 sRAGE 增加可能通过减少癌症风险来改变 糖尿病前期患者的 AGE-RAGE 毒性。本研究的目的是评估 TRF 对 AGE-RAGE 对乳腺癌风险较高的女性的毒性，并探讨 TRF 的机制意义 在饮食 AGE 小鼠肿瘤模型中诱导 sRAGE。我们提出两个具体目标；进行试点 随机对照试验 (RCT) 旨在测量 TRF 对 AGE-RAGE 毒性的影响 患有糖尿病前期 (SA1) 的绝经后妇女，并检查 sRAGE 上调机制 体内对 TRF 的反应 (SA2)。 确定疾病危险因素对于修改旨在降低乳腺癌风险的治疗方法至关重要 在弱势群体中。 sRAGE 已被确定对糖尿病和乳腺癌具有重要的临床意义。作为 糖尿病的流行持续扩大，导致乳腺癌高危女性人数增加， 确定 sRAGE 响应 TRF 增加的机制和类型将为更大的研究提供平台 干预研究。此类研究旨在进一步确定针对环境问题的潜力 AGE 作为通过禁食预防癌症的策略。