Peptide therapy for age-associated gut dysmotility

肽疗法治疗与年龄相关的肠道动力障碍

• 批准号: 10575265
• 负责人: SUSHIL K MAHATA
• 金额: $ 22.28万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575265
• 关键词: Acetylcholine; Affect; Age; Aging; Agonist; Autopsy; Brain; Catecholamines; Cells; Central Nervous System; Cholinergic Receptors; Chromogranin A; Chronic; Clinical Chemistry; Constipation; Cost of Illness; Development; Diabetes Mellitus; Diarrhea; Disease; Dopamine; Elderly; Enteral; Enteric Nervous System; Enterochromaffin Cells; Failure; Fecal Incontinence; Frequencies; Ganglia; Gastric Emptying; Gastrointestinal Diseases; Gastroparesis; Half-Life; Health; Hematology; Histologic; Hormones; Human; Hypertension; Incidence; Infection; Innate Immune System; Interneurons; Interstitial Cell of Cajal; Intestinal Pseudo-Obstruction; Intestinal permeability; Intramuscular; Knock-out; Knockout Mice; Light; Link; Liquid substance; Maintenance; Malabsorption Syndromes; Measures; Mediating; Metabolic Diseases; Molecular; Motor Neurons; Mucous Membrane; Mus; Muscle; Muscle Cells; Myenteric Plexus; Neurites; Neuroglia; Neurons; Neurotransmitters; Nutrient; Obese Mice; Organ; Outcome; Pacemakers; Pathway interactions; Peptides; Phenotype; Physiology; Plasma; Population; Prevention; Process; Production; Quality of life; Receptor Signaling; Regulation; Resistance; Risk; Scientist; Serotonin; Serotonin Receptors 5-HT4; Smooth Muscle Myocytes; Solid; Stimulus; Stomach; Submucosa; Submucous Plexus; Substance P; Supplementation; Testing; Therapeutic; Tissues; Toxic effect; Translating; Visual; Work; antagonist; cell motility; cholinergic; combat; disabling symptom; experience; experimental study; improved; microbiome composition; mimetics; motility disorder; neural; neuronal cell body; novel therapeutics; nutrient absorption; pharmacophore; prevent; receptor; small molecule; targeted treatment; therapeutic target; transmission process; tumor growth

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.

项目概要/摘要 衰老与胃排空液体和固体的速率以及频率的降低有关 在人类中，肠道蠕动障碍会加剧感染，导致营养吸收不良， 并表现为虚弱症状，如胃轻瘫、假性肠梗阻、腹泻、 便秘、先天性巨结肠症和大便失禁 大约 20% 的老年人患有慢性疾病。 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。 每年数十亿的肠道运动受到平滑肌细胞、间质细胞的协调活动的调节。 Cajal (ICC)、中枢神经系统神经元和肠神经系统中的运动神经元 (ENS，“ ENS 运动神经元释放兴奋性神经递质，例如乙酰胆碱 (ACh)。 和 P 物质 (SP) 或 5-羟色胺 (5-HT) 4 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中，可抑制乙酰胆碱的释放。 内在胆碱能运动神经元通过激活连接前 D2R 来增强肠道运动。 通过激活 5-HT4R 引起 ACh 释放，CgA 被蛋白水解加工成多种生物活性。 活性肽包括儿茶素（CST：hCgA352-372）最近，我们发现肠道动力是。 CST-KO 小鼠中受损，补充 CST 后恢复。 小鼠表现出以下表型：（i）胃增大（胃轻瘫），（ii）胃排空延迟，（iii） 5-HT，和 (iv) 增加的 DA 作为减少的 ACh 受体 (AChR) 的短期拮抗剂， 抑制儿茶酚胺分泌和长效激动剂，刺激ACh分泌，因此，CST。 可能通过增加肌间神经丛的 ACh 分泌并减少 因为我们发现老年 WT 小鼠的血浆 CST 降低，而肠道中的 CST 降低。 对于老年小鼠，我们认为 CST 在减轻肠道动力障碍方面发挥作用，我们制定了四种方案。 可能介导 CST 对肠道运动调节的独立协同假设：(i) 激活 AChR，(ii) 促进肠嗜铬细胞产生 5-HT，(iii) ENS 抑制 DA 产生， (iv) 通过增加耐受性来维持肌内 ICC (ICC-IM) 群体以验证或反驳。 针对上述假设，我们提出了两个具体目标的实验： 目标一：检验假设 CST 通过促进 AChR 信号传导来改善衰老小鼠的肠道蠕动和胃排空， 增加 5-HT 的产生，抑制 DA 的释放，并防止 ICC 群体的损失。 将 CST 启发的疗法用于对抗与年龄相关的肠道运动障碍：影响。 该提案的首要重点是生成有关 CST 及其模拟物影响的重要信息 我们的研究将是第一个将 CST 及其模拟物直接联系起来的研究。 肠道动力，并可能建立 CST 途径作为肠道动力的治疗靶标。 是积极的，那么新的治疗途径可能会出现，从而使冒险变得值得。