Peptide therapy for age-associated gut dysmotility

肽疗法治疗与年龄相关的肠道动力障碍

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要衰老与液体和固体胃排空速率的降低有关蠕动收缩。在人类中，肠道潜在感染的运动障碍会导致营养吸收不良，并具有令人衰弱的符号，例如胃轻瘫，肠道假obstruction，腹泻，便秘，Hirschprung氏病和粪便失禁。大约20％的老年人经历了慢性深刻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 每年十亿美元。肠道运动受平滑肌细胞，间质细胞的协调活性调节肠神经系统中的Cajal（ICC），中枢神经系统神经元和运动神经元（ENS，“ 肠道的大脑”）。ENS运动神经元释放兴奋性神经递质，例如乙酰胆碱（ACH）和物质P（SP）。 5-羟色胺或5-羟色胺（5-HT）4受体（5-HT4R）和多巴胺（DA）2 受体（D2R）在肠神经节内的神经运动中广泛表达。 DA抑制ACH从固有的胆碱能运动神经元通过激活结构前的D2RS。 5-HT通过通过激活5-HT4R引起ACH释放。 CGA在几个生物学上被蛋白水解处理活性肽在内，包括Catestatin（CST：HCGA352-372）。最近，我们发现肠道运动是在CST-KO小鼠中妥协，该小鼠补充了CST后恢复了。此外，CST-KO 小鼠显示以下表型：（i）降级增加（胃轻瘫），（ii）胃排空延迟，（iii）降低5-HT，（IV）增加了DA。 CST充当ACH受体（ACHR）的短期拮抗剂，抑制儿茶酚胺分泌和长期激动剂，刺激ACH分泌。因此，CST 可能通过增加肌丛的ACH分泌并减少来调节肠道运动障碍 Da的分泌。由于我们发现年龄较大的WT小鼠的血浆CST降低，并且CST降低了。年长的老鼠，我们认为CST将在衰减肠道不良运动中发挥作用。我们已经配制了四个独立的协同假设可能介导CST的肠运动调节：（i）激活 ACHR，（ii）通过肠球毒细胞促进5-HT的产生，（iii）通过ENS抑制DA的产生，（iv）通过增加公差来维持肌内ICC（ICC-IM）人群。进行验证或驳斥上述假设，我们提出了两个具体目的的实验：目标I：检验以下假设： CST通过促进ACHR信号传导来改善衰老小鼠的肠道运动和胃排空增加5-HT的产生，抑制DA释放并防止ICC人群损失。 AIM II：将CST启发的疗法转化为对抗年龄相关的肠道运动障碍。影响：该提案的总体重点是生成有关CST及其Mimetics影响的重要信息缓解与年龄相关的肠道运动障碍。我们的研究将是第一个直接连接CST及其模拟物的研究肠运动性，并有可能建立CST途径作为肠道运动的治疗靶标。如果结果是积极的，那么新的治疗途径可能会曝光，使风险值得。