Peptide therapy for age-associated gut dysmotility

项目摘要/摘要 衰老与胃液体和固体的排空率以及胃排空频率的降低有关。 蠕动收缩。在人类中，肠道动力障碍会加剧感染，导致营养吸收不良， 出现胃瘫、肠假性梗阻、腹泻等虚弱症状， 便秘、先天性巨结肠和大便失禁。约20%的老年人患有慢性病 严重影响健康和生活质量的便秘。在美国，胃肠道疾病的费用为135.9美元 每年10亿美元。肠运动受平滑肌细胞、间质细胞协调活动的调节 Cajal(ICCs)、中枢神经系统神经元和肠神经系统运动神经元(ENS) 肠脑“)。ENS运动神经元释放兴奋性神经递质，如乙酰胆碱(ACh) 和P物质(SP)。5-羟色胺受体(5-HT4R)和多巴胺(DA)2 受体(D2R)广泛表达于肠神经节内的神经突起。DA抑制ACh的释放 激活连接前D2Rs的内源性胆碱能运动神经元。5-羟色胺通过增强肠道动力 通过激活5-HT4R激活ACh释放。CGA被蛋白质降解处理成几种生物 活性多肽包括儿茶素(CST：hCgA352-372)。最近，我们发现肠道动力是 在CST-KO小鼠中受损，补充CST后恢复。此外，CST-KO 小鼠表现出以下表型：(I)胃增大(胃轻瘫)，(Ii)胃排空延迟，(Iii) 降低5-羟色胺，(Iv)增加多巴胺。CST作为ACh受体(AChR)的短期拮抗剂， 抑制儿茶酚胺和一种长期的激动剂，刺激ACh的分泌。因此，CST 可能通过增加肌间神经丛ACh的分泌和减少ACh的分泌来调节肠道运动障碍 多巴胺的分泌。由于我们发现老年WT小鼠血浆CST降低，肠道CST降低 对于年龄较大的小鼠，我们推断CST将在减弱肠道运动障碍方面发挥作用。我们已经制定了四个方案 可能介导CST调节肠道运动的独立协同假说：(I)激活 ACHR，(Ii)肠嗜铬细胞促进5-羟色胺的产生，(Iii)ENS抑制DA的产生， 以及(Iv)通过增加耐受性来维持肌内ICC(ICC-IM)种群。证实或驳斥 在上述假设下，我们提出了两个具体的实验目的：目的一：检验假设 CST通过促进AChR信号通路改善衰老小鼠肠动力和胃排空， 增加5-羟色胺的产生，抑制DA的释放，防止ICC种群的丢失。目标二： 翻译CST启发的疗法来对抗与年龄相关的肠道运动障碍。影响： 这项提案的主要重点是产生关于科技委及其模仿学影响的重要信息 论年龄相关性胃肠动力障碍的缓解。我们的研究将是第一次将CST和它的模拟直接联系起来 肠道运动，并有可能建立CST通路作为肠道运动的治疗靶点。如果结果是 如果是积极的，那么新的治疗途径可能会浮出水面，使风险变得值得。

PROJECT SUMMARY/ABSTRACT Aging is associated with reductions in the rates of gastric emptying for liquids, and solids, as well as the frequency of peristaltic contractions. In humans, dysmotility of the gut potentiates infections, causes nutrient malabsorption, and manifests with debilitating symptoms, such as gastroparesis, intestinal pseudo-obstruction, diarrhea, constipation, Hirschprung’s disease, and fecal incontinence. About 20% of older adults experience chronic constipation that profoundly affect health and quality of life. In the USA, gastrointestinal diseases cost $135.9 billion annually. Gut motility is regulated by coordinated activities from smooth muscle cells, interstitial cells of Cajal (ICCs), central nervous system neurons and motor neurons in the enteric nervous system (ENS, “the brain of the gut”). ENS motor neurons release excitatory neurotransmitters, such as acetylcholine (ACh) and substance P (SP). Serotonin or 5-hydroxytryptamine (5-HT) 4 receptor (5-HT4R) and dopamine (DA) 2 receptor (D2R) are widely expressed in neurites within enteric ganglia. DA inhibits release of ACh from intrinsic cholinergic motor neurons by activating pre-junctional D2Rs. 5-HT enhances gut motility by evoking ACh release via activation of 5-HT4R. CgA is proteolytically processed to several biologically active peptides including catestatin (CST: hCgA352-372). Recently, we found that gut motility is compromised in CST-KO mice, which was restored after supplementation with CST. Furthermore, CST-KO mice show the following phenotypes: (i) enlarged stomach (gastroparesis), (ii) delayed gastric emptying, (iii) decreased 5-HT, and (iv) increased DA. CST acts as a short-term antagonist to ACh receptor (AChR), inhibiting catecholamine secretion and a long- term agonist, stimulating ACh secretion. Therefore, CST might modulate gut dysmotility by increasing secretion of ACh at the myenteric plexus and decreasing secretion of DA. Since we found decreased plasma CST in older WT mice and decreased CST in the gut of older mice, we reason that CST would play a role in attenuating gut dysmotility. We have formulated four independent synergistic hypotheses that may mediate CST’s regulation of gut motility: (i) activation of AChR, (ii) promotion of 5-HT production by enterochromaffin cells, (iii) inhibition of DA production by ENS, and (iv) maintenance of intramuscular ICC (ICC-IM) population by increasing tolerance. To validated or refute the above hypotheses, we have proposed experiments in two specific aims: Aim I: Test the hypothesis that CST improves gut motility and gastric emptying in aging mice by promoting AChR signaling, increasing 5-HT production, inhibiting DA release, and preventing loss of ICC population. Aim II: Translate CST-inspired therapeutics to combat age-associated gut dysmotility. IMPACT: The overarching focus of this proposal is to generate important information on the impact of CST and its mimetics on alleviation of age-associated gut dysmotility. Our study will be the first to directly link CST and its mimetics to gut motility, and potentially establish CST pathway as a therapeutic target for gut motility. If the outcome is positive, then new therapeutic avenues could come to light, making the risk worthwhile.