Novel role of Ezh2 in age-related gastric motility dysfunctions

Ezh2 在年龄相关胃动力功能障碍中的新作用

• 批准号: 10379343
• 负责人: Yujiro NA Hayashi
• 金额: $ 35.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379343
• 关键词: Address; Age; Aging; Anorexia; Body Weight; Cell Aging; Cells; Complex; Consumption; Data; Dependence; Dietary intake; Differentiated Gene; Elderly; Enhancers; Enteral; Epigenetic Process; Family; Functional disorder; Gastric Emptying; Gastric Tissue; Gastrointestinal tract structure; Genomics; Homologous Gene; Immune; Impairment; Individual; Inflammatory; Interstitial Cell of Cajal; Knowledge; Lead; Link; Longevity; Malignant Neoplasms; Mechanics; Mediating; Medical; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Muscle Contraction; Neuromodulator; Neurons; Organ; PRC1 Protein; Pacemakers; Pathway interactions; Pharmacology; Phase; Prevention; Quality of life; Reflex control; Regulation; Reporting; Repression; Role; Satiation; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Sphincter; Stomach; Symptoms; Therapeutic; Tissues; Up-Regulation; WNT Signaling Pathway; Work; age related; aged; base; beta catenin; cell motility; cholinergic; dietary; early satiety; epigenetic regulation; frailty; gene repression; healthy aging; histone methyltransferase; improved; integration site; interstitial cell; medical attention; mortality; motor disorder; neurotransmission; new therapeutic target; nodal myocyte; novel; prevent; recruit; reduced food intake; sarcopenia; self-renewal; senescence; stem cell aging; stem cell self renewal; stem cells; weight maintenance

Age-related gastric motor dysfunctions include reduced compliance and impaired slow wave activity. However, these dysfunctions are often underestimated due in part to nonspecific symptoms and lack of sufficient medical attention. Although these conditions are not themselves fatal, they have been shown to contribute to early satiety and consequent reduced food intake. Surprisingly, recent reports have linked low dietary intake to increased cancer mortality and overall mortality in elderly individuals and aged mice, suggesting that reduced food intake due to gastric dysfunctions may contribute to increased overall mortality in elderly individuals. Thus, a growing body of evidence indicates the significance of studying age-related gastric motor dysfunctions to promote healthy aging. Previously we reported a profound age-related loss of interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells of the GI tract. ICC loss was accompanied by a depletion of ICC stem cells (ICC-SC); and these changes could be linked to specific gastric dysfunctions and reduced food intake. A critical gap in our knowledge is the lack of understanding of the mechanisms of age-related ICC loss and related gastric motor dysfunctions. Stem cell senescence has been proposed as a major factor of aging-related organ dysfunctions, and in preliminary studies we found that overactive Wnt/β-catenin signaling can indeed lead to ICC-SC senescence via increased Trp53. Another important mechanism proposed to underlie stem cell senescence is altered function of histone methyltransferase enhancer of zeste homolog 2 (Ezh2), which we found to be upregulated in senescent ICC-SC and gastric tissues obtained from older mice and individuals. However, the relationship between Wnt-induced senescence and Ezh2 remains unclear. Therefore, my overall hypothesis is that ICC-SC senescence, a putative mechanism of age-related ICC loss, is due to overactive Wnt signaling-induced recruitment of Ezh2 and consequent repression of genes important for ICC- SC self-renewal and differentiation; and senescence can be prevented by Ezh2 inhibition. Specific Aim 1 is to provide definitive evidence that overactive Wnt signaling can lead to ICC-SC senescence via Trp53 upregulation. Specific Aim 2 is to unravel epigenetic mechanisms of ICC- SC senescence underlying aging-associated ICC depletion. Specific Aim 3 is to determine the functional consequence of aging-associated ICC depletion. This project may reveal a novel, pharmacologically realizable therapeutic approach to prevent ICC-SC senescence and age- related gastric dysfunctions leading to improved quality of life. This project also aims to discover a previously unrecognized mechanism of stem cell aging, which may be of general significance.

与年龄相关的胃运动功能障碍包括顺应性降低和慢波受损 活动。然而，这些功能障碍往往被低估，部分原因是非特异性 症状和缺乏足够的医疗照顾。虽然这些条件本身并不 致命的是，它们已被证明会导致过早饱腹感，从而减少食物摄入量。 令人惊讶的是，最近的报告将低饮食摄入量与癌症死亡率和癌症死亡率增加联系起来。 老年人和老年小鼠的总体死亡率，表明由于食物摄入量减少 胃功能障碍可能导致老年人总体死亡率增加。因此，一个 越来越多的证据表明研究与年龄相关的胃运动的重要性 功能障碍，促进健康老龄化。之前我们报道过与年龄相关的严重丧失 Cajal 间质细胞 (ICC)、胃肠道起搏器和神经调节细胞。 ICC损失 伴随着 ICC 干细胞 (ICC-SC) 的耗竭；这些变化可能是 与特定的胃功能障碍和食物摄入量减少有关。我们知识中的一个关键差距是 对与年龄相关的 ICC 丢失和相关胃运动的机制缺乏了解 功能障碍。干细胞衰老已被认为是衰老相关器官的主要因素 功能障碍，在初步研究中我们发现过度活跃的 Wnt/β-catenin 信号传导可以 确实通过增加 Trp53 导致 ICC-SC 衰老。另一个重要机制 研究表明，组蛋白甲基转移酶的功能改变是干细胞衰老的基础 zeste 同源物 2 (Ezh2) 的增强子，我们发现其在衰老 ICC-SC 中表达上调 以及从老年小鼠和个体中获得的胃组织。然而，之间的关系 Wnt 诱导的衰老和 Ezh2 仍不清楚。因此，我的总体假设是 ICC-SC 衰老是与年龄相关的 ICC 丧失的一种假定机制，是由于 Wnt 过度活跃所致 信号诱导的 Ezh2 募集以及随后对 ICC 重要基因的抑制 SC的自我更新和分化；抑制 Ezh2 可以预防衰老。 具体目标 1 是提供明确的证据，证明过度活跃的 Wnt 信号传导可导致 ICC-SC 通过 Trp53 上调来衰老。具体目标 2 是解开 ICC-的表观遗传机制 SC 衰老是与衰老相关的 ICC 耗竭的基础。具体目标 3 是确定 衰老相关 ICC 耗竭的功能后果。这个项目可能会揭示一部小说， 预防 ICC-SC 衰老和年龄增长的药物可实现的治疗方法 相关胃功能障碍可改善生活质量。该项目还旨在发现 一种以前未被认识的干细胞衰老机制，可能具有普遍意义。