Gut Neuroendocrine Cell Signaling and Obesity

描述（由申请人提供）： 肥胖是一种常见、严重且昂贵的疾病，影响33%的美国公民和37%的VA患者。虽然治疗方法仍然难以捉摸，但最近的科学证据表明，肠内分泌细胞-肠道的感觉细胞-是潜在的解决方案。已知这些细胞分泌几种神经肽，这些神经肽是饱腹感的有效诱导剂，如胆囊收缩素（CCK）、胰高血糖素样肽-1（GLP-1）和肽YY（PYY），并且它们的感觉机制一直是深入研究的主题。然而，这些细胞如何将它们的感觉信号传递给神经元和其他细胞在很大程度上是未知的。 我们最近开发了新的转基因小鼠模型来研究这些细胞通过表达增强型绿色荧光蛋白（eGFP）在CCK或PYY含细胞。eGFP模型使我们能够发现肠内分泌细胞具有突出的基底细胞质突起，其具有与神经元轴突相似的特征。我们发现，这些基础的细胞质过程，直接连接到神经传入和传出神经支配肠粘膜。 本提案旨在阐明这种联系的功能。我们的中心假设是，基底细胞质过程是必不可少的肠内分泌细胞和感觉神经元之间的分子信息交换。这一假设是建立在PI实验室产生的初步数据基础上的，并将通过追求以下特定目标进行测试：目标1是表征肠内分泌细胞和感觉神经元之间的连接目标2是确定肠内分泌细胞胞质过程的形成是如何调节的目的3是确定饮食诱导的肥胖对神经系统的影响，肠内分泌的联系我们预期，肠神经内分泌信号的特征将有助于发展调节感觉信息传递的策略从肠内分泌细胞到神经元，反之亦然。由于这些感觉信号最终参与食物摄入和食欲的调节，因此阐明调节这种联系的机制可以为治疗肥胖提供新的治疗方法。

DESCRIPTION (provided by applicant): Obesity is a common, serious, and costly disease that affects 33% of US citizens and 37% of VA patients. Although therapeutic treatments remain elusive, recent scientific evidence has pointed to enteroendocrine cells - sensory cells of the gut - as potential solutions. These cells are known to secrete several neuropeptides that are potent inducers of satiety, like cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), and their sensory mechanisms have been the subject of intensive investigation. However, how these cells transduce their sensory signals onto neurons and other cells is largely unknown. We recently developed novel transgenic mouse models to study these cells by expressing enhanced green fluorescent protein (eGFP) in CCK- or PYY-containing cells. The eGFP models allowed us to discover that enteroendocrine cells have prominent basal cytoplasmic processes with similar features to neuronal axons. These basal cytoplasmic processes, we found, directly connect to neuronal afferents and efferents innervating the gut mucosa. The present proposal is designed to elucidate the function of this connection. Our central hypothesis is that basal cytoplasmic processes are essential in the exchange of molecular information between enteroendocrine cells and sensory neurons. This hypothesis is built on preliminary data produced in the PI's laboratory and will be tested by pursuing the following specific aims: ¿ Aim 1 is to characterize the connection between enteroendocrine cells and sensory neurons ¿ Aim 2 is to determine how the formation of enteroendocrine cell cytoplasmic processes is regulated ¿ Aim 3 is to define the effects of diet-induced obesity on the neuro-enteroendocrine connection We anticipate that the characterization of gut neuroendocrine signaling will facilitate the development of strategies to modulate the transmission of sensory information from enteroendocrine cells to neurons and vice versa. Because these sensory signals ultimately participate in the regulation of food intake and appetite, elucidating the mechanisms that regulate this connection can provide novel therapeutic approaches to treat obesity.