Novel role of Ezh2 in age-related gastric motility dysfunctions

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，部分原因是由于非特异性 症状和缺乏足够的医疗照顾。虽然这些条件本身并不 它们是致命的，已被证明会导致过早的饱腹感和随之而来的食物摄入量减少。 令人惊讶的是，最近的报告将低饮食摄入量与癌症死亡率增加联系起来， 老年个体和老年小鼠的总体死亡率，表明由于 胃功能障碍可能导致老年人总体死亡率增加。因此 越来越多的证据表明，研究年龄相关的胃运动具有重要意义 促进健康老龄化。之前我们报道了一种与年龄相关的严重的 Cajal间质细胞（ICC），胃肠道的起搏细胞和神经调节细胞。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。我们知识上的一个关键差距是 对年龄相关的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被认为是衰老相关器官的一个主要因素 功能障碍，在初步研究中，我们发现过度活跃的Wnt/β-catenin信号转导可以 确实通过增加Trp 53导致ICC-SC衰老。另一个重要机制 组蛋白甲基转移酶的功能改变被认为是干细胞衰老的基础 zeste增强子同源物2（Ezh 2），我们发现它在衰老的ICC-SC中上调 以及从老年小鼠和个体获得的胃组织。然而， Wnt诱导的衰老和Ezh 2仍不清楚。因此，我的总体假设是， ICC-SC衰老是年龄相关性ICC丢失的一种假定机制，是由于过度活跃的Wnt 信号传导诱导Ezh 2的募集和随后对ICC重要基因的抑制， SC自我更新和分化;和衰老可以通过Ezh 2抑制来防止。 具体目标1是提供明确的证据，过度活跃的Wnt信号传导可导致ICC-SC 通过Trp 53上调衰老。具体目标2是解开ICC的表观遗传机制- SC衰老是衰老相关ICC耗竭的基础。具体目标3是确定 衰老相关的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衰老和老化的可行治疗方法- 相关的胃功能障碍，从而改善生活质量。该项目还旨在发现 一种以前未被认识到的干细胞衰老机制，可能具有普遍意义。

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.