Developmental Origins of Functional Dyspepsia

功能性消化不良的发育起源

• 批准号: 8095854
• 负责人: SUSHIL K SARNA
• 金额: $ 38.25万
• 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/8095854
• 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; 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％的美国人群。功能性消化不良的两个主要症状是上腹疼痛，由于摄入饭菜而夸大了胃排空。这些症状的病因尚不清楚，这阻碍了开发有效治疗剂的努力。研究这些症状的病因的主要障碍是缺乏患者和正常受试者的组织可用性来检验新的假设并在细胞，分子和遗传水平进行研究。同时模仿功能性消化不良的两种症状的动物模型迫切需要发展该领域。 这些基因是从两个父母那里继承的。但是，DNA需要表观遗传机制来编程单个基因的表达。该编程是在发展的胎儿和新生儿阶段完成的。表观遗传编程的信息也从父母那里继承下来。它的目标是确保胎儿和新生儿的生存以及成年内器官的正常功能。但是，如果母亲或新生儿暴露于严重的心理或炎症压力，则表观遗传机制适应以确保在不利条件下胎儿或新生儿的立即存活。但是，这种基因的重编程持续到成年后，可能导致复杂的成人疾病，例如糖尿病，高血压和癌症。这种现象称为新生儿或胎儿编程。 该提议中我们的假设是：1）在脆弱的新生儿发育阶段的结肠炎症引起了功能困难的两种基本症状，延迟的胃排空和对胃延伸的胃肠过敏性延迟。 2）胃排空的延迟是由于胃平滑肌细胞中激发 - 收缩偶联的钥匙细胞信号蛋白的基因表达改变。 3）内脏超敏反应是由于胃特异性背神经神经元的兴奋性增加所致。 4）通过新生儿编程对特定基因的HPA轴调节和表观遗传调节介导了这些效果。我们将使用最先进的细胞，分子和表观遗传学方法在大鼠中检验这些假设。我们的发现有望产生对肠道主要疾病的细胞机制的新见解，并确定治疗剂的潜在表观遗传和药理靶标。 公共卫生相关性：功能性消化不良是肠道的主要疾病。它折磨了约15％至25％的美国人口。功能性消化不良的患者表现出腹痛和胃排空延迟的症状。目前，该疾病还没有有效的治疗方法。我们的发现将阐明这种疾病的基础机制，并确定开发有效治疗剂的靶标。