Developmental Origins of Functional Dyspepsia

功能性消化不良的发育起源

• 批准号: 8252137
• 负责人: SUSHIL K SARNA
• 金额: $ 33.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252137
• 关键词: Abdominal Pain; Abnormal Cell; Adult; Affect; Animal Model; Asthma; Barker Hypothesis; Biochemical; Biological Markers; Body Weight decreased; Cell physiology; Cells; Clinical; Clinical Trials; Complex; Coupling; Cystic Fibrosis; DNA; Development; Diabetes Mellitus; Disease; Disease remission; Dyspepsia; Ensure; Environmental Risk Factor; Epigastric; Epigenetic Process; Eructation; Etiology; Exhibits; Fetus; Functional disorder; Gastric Emptying; Gastroenterologist; Gastrointestinal Diseases; Gastroparesis; Gene Expression; Gene Mutation; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Histone Deacetylase Inhibitor; Hormones; Human; Hypersensitivity; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Ingestion; Inherited; Intestines; Investigation; Laws; Life; Longitudinal Studies; Malignant Neoplasms; Mediating; Molecular; Molecular Genetics; Monozygotic Twinning; Monozygotic twins; Mothers; Nausea and Vomiting; Neonatal; Neurons; Neurotransmitters; Organ; Pain; Parents; Patients; Phenotype; Physiological; Population; Process; Puberty; Rattus; Regulation; Relapse; Scientist; Sickle Cell Anemia; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; Staging; Stomach; Stress; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transferase; Trauma; Visceral; base; cell motility; effective therapy; fetal; fetal programming; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; insight; neonate; novel; programs; psychologic; public health relevance; research study; response; spinal nerve posterior root

DESCRIPTION (provided by applicant): Functional Dyspepsia is a major functional bowel disorder that affects about 15% to 25% of the U.S. population. The two primary symptoms of Functional Dyspepsia are upper abdominal pain that is exaggerated by ingestion of a meal, and delayed gastric emptying. The etiology of these symptoms is not known, which has hampered efforts to develop effective therapeutic agents. A major obstacle in investigation of the etiologies of these symptoms is the lack of availability of tissues from patients and normal subjects to test novel hypothesis and conduct studies at the cellular, molecular and genetic levels. An animal model that concurrently mimics both the symptoms of Functional Dyspepsia is desperately needed to advance the field. The genes are inherited from two parents. However, the DNA requires epigenetic mechanisms to program the expression of individual genes. This programming is accomplished during the fetal and neonatal stages of developments. The information for epigenetic programming is also inherited from the parents. Its goal is to ensure survival of the fetus and the neonate, and normal functioning of the organs in adulthood. However, if the mother or the neonate is exposed to severe psychological or inflammatory stress, the epigenetic mechanisms adapt to ensure immediate survival of the fetus or the neonate under adverse conditions. However, such reprogramming of the genes persists into adulthood and it may result in complex adult diseases, such as diabetes, hypertension and cancer. This phenomenon is called neonatal or fetal programming. Our hypotheses in this proposal are: 1) Colonic inflammation during the vulnerable neonatal stage of development induces the two cardinal symptoms of Functional Dyspepsia, delayed gastric emptying and visceral hypersensitivity to gastric distension in adulthood. 2) The delay in gastric emptying is due to altered gene expression of key cell signaling proteins of the excitation-contraction coupling in gastric smooth muscle cells. 3) Visceral hypersensitivity is due to increase in the excitability of gastric-specific dorsal root ganglionic neurons. 4) The modulation of HPA-axis and epigenetic regulation of specific genes by neonatal programming mediate these effects. We will test these hypotheses in rats using state-of-the-art cellular, molecular and epigenetic approaches. Our findings are expected to yield novel insights into the cellular mechanisms of a major disorder of the gut and identify potential epigenetic and pharmacologic targets for therapeutic agents. PUBLIC HEALTH RELEVANCE: Functional dyspepsia is a major disorder of the gut. It afflicts about 15% to 25% of the U.S. population. The patients with Functional Dyspepsia display symptoms of abdominal pain and delayed gastric emptying. Currently, there is no effective treatment for this disorder. Our findings will elucidate the mechanisms underlying this disorder and identify targets for the development of effective therapeutic agents.

描述（由申请人提供）：功能性消化不良是一种主要的功能性肠道疾病，影响约 15% 至 25% 的美国人口。功能性消化不良的两个主要症状是上腹部疼痛（因进食而加剧）和胃排空延迟。这些症状的病因尚不清楚，这阻碍了开发有效治疗药物的努力。研究这些症状的病因学的一个主要障碍是缺乏来自患者和正常受试者的组织来测试新的假设并在细胞、分子和遗传水平上进行研究。迫切需要一种同时模拟功能性消化不良两种症状的动物模型来推进该领域的发展。 这些基因遗传自两个父母。然而，DNA 需要表观遗传机制来编程单个基因的表达。这种编程是在胎儿和新生儿发育阶段完成的。表观遗传编程的信息也是从父母那里继承的。其目标是确保胎儿和新生儿的存活以及成年期器官的正常功能。然而，如果母亲或新生儿面临严重的心理或炎症应激，表观遗传机制会进行调整，以确保胎儿或新生儿在不利条件下立即存活。然而，这种基因重编程会持续到成年，并可能导致复杂的成人疾病，如糖尿病、高血压和癌症。这种现象称为新生儿或胎儿编程。 我们在该提案中的假设是：1）脆弱的新生儿发育阶段的结肠炎症会诱发功能性消化不良的两个主要症状，即胃排空延迟和成年后对胃扩张的内脏过敏。 2)胃排空延迟是由于胃平滑肌细胞中兴奋-收缩耦合的关键细胞信号蛋白的基因表达改变所致。 3）内脏过敏是由于胃特异性背根神经节神经元兴奋性增加所致。 4) HPA 轴的调节和新生儿编程对特定基因的表观遗传调节介导了这些效应。我们将使用最先进的细胞、分子和表观遗传学方法在大鼠身上测试这些假设。我们的研究结果有望对肠道主要疾病的细胞机制产生新的见解，并确定治疗药物的潜在表观遗传和药理学靶点。 公众健康相关性：功能性消化不良是一种主要的肠道疾病。它困扰着大约 15% 至 25% 的美国人口。功能性消化不良患者表现出腹痛和胃排空延迟的症状。目前，这种疾病没有有效的治疗方法。我们的研究结果将阐明这种疾病的机制，并确定开发有效治疗药物的目标。