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道疾病，约占美国人口的15%至25%。功能性消化不良的两个主要症状是上腹部疼痛，因进食而加重，以及胃排空延迟。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。研究这些症状病因的一个主要障碍是缺乏来自患者和正常受试者的组织来检验新的假设并在细胞、分子和遗传水平上进行研究。目前迫切需要一种同时模拟功能性消化不良症状的动物模型来推进这一领域。这些基因从父母双方遗传而来。然而，DNA需要表观遗传机制来编程单个基因的表达。这种规划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遗传来的。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，表观遗传机制适应以确保胎儿或新生儿在不利条件下的即时生存。然而，这种基因的重新编程会持续到成年，并可能导致复杂的成人疾病，如糖尿病、高血压和癌症。这种现象被称为新生儿或胎儿规划。我们的假设是：1)脆弱的新生儿发育阶段的结肠炎症诱发了成年期功能性消化不良、胃排空延迟和内脏对胃膨胀的超敏反应这两种主要症状。2)胃排空延迟是由于胃平滑肌细胞兴奋-收缩偶联关键细胞信号蛋白基因表达改变所致。3)内脏超敏是由于胃特异性背根神经节神经元兴奋性的增加。4)新生儿编程对hpa轴的调控和特定基因的表观遗传调控介导了这些效应。我们将用最先进的细胞、分子和表观遗传学方法在大鼠身上测试这些假设。我们的发现有望对一种主要肠道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。

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.