Developmental Origins of Functional Dyspepsia

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，这是加剧了摄入的一餐，和延迟胃排空。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。这些症状的病因学研究的主要障碍是缺乏来自患者和正常受试者的组织的可用性，以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。 这些基因是从双亲遗传的。然而，DNA需要表观遗传机制来编程单个基因的表达。这种编程在胎儿和新生儿发育阶段完成。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，以及成年后器官的正常功能。然而，如果母亲或新生儿暴露于严重的心理或炎症应激，表观遗传机制会适应，以确保胎儿或新生儿在不利条件下立即存活。然而，这种基因的重新编程持续到成年，可能导致复杂的成人疾病，如糖尿病，高血压和癌症。这种现象被称为新生儿或胎儿编程。 我们的假设是：1）新生儿期的结肠炎症导致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高敏感性。2)胃排空延迟是由于胃平滑肌细胞中兴奋-收缩偶联的关键细胞信号蛋白的基因表达改变。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。4)HPA轴的调制和新生儿编程介导的特定基因的表观遗传调控这些影响。我们将使用最先进的细胞，分子和表观遗传方法在大鼠中测试这些假设。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。 公共卫生相关性：功能性消化不良是一种主要的肠道疾病。它困扰着大约15%到25%的美国人口。功能性消化不良患者表现为腹痛和胃排空延迟。目前，对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，并确定有效的治疗药物的发展目标。

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.