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.

项目总结/文摘