Development and plasticity of ICC

ICC的发展与可塑性

• 批准号: 7235349
• 负责人: Sean M Ward
• 金额: $ 18.01万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7235349
• 关键词: biological signal transduction; developmental genetics; developmental neurobiology; electron microscopy; electrophysiology; enteric nervous system; gastrointestinal motility /pressure; immunocytochemistry; immunoelectron microscopy; intestines; laboratory mouse; ligands; neural plasticity; neural transmission; neurogenesis; neuroregulation; phenotype; protein tyrosine kinase; smooth muscle; stem cell factor; voltage /patch clamp

Tissues isolated from different regions of the gastrointestinal tract, display spontaneous electrical and mechanical activity. When contractions and membrane potential are recorded simultaneously each contraction is triggered by a long lasting wave of depolarization that have been termed slow waves. The origin and basis for the generation of slow wave activity has been debated for many years but it is now widely accepted that these pacemaker potentials arise from a separate group of cells, known as interstitial cells of Cajal (ICC). The mechanical activity of most smooth muscle cells is also modified by autonomic or enteric nerves. Previously it was thought that neurotransmission in smooth muscles occurred by simple diffusion. However, it appears that nerve terminals, rather than communicating directly with smooth muscle cells, form close synaptic relationships with ICC in several regions of the GI tract. These contacts are necessary for coordinated motor neurotransmission in GI muscles. Motility disorders have traditionally been characterized as either myopathic or neuropathic in origin, although a large majority of patients that suffer from these disorders do not display obvious histopathological changes in either enteric nerves or smooth muscle cells in biopsies. The discovery that ICC express the receptor tyrosine kinase, Kit has provided pathologists and gastroenterologists with a means to access the changes in ICC that occur in patients with both congenital or acquired motility disorders. Several recent clinical studies have indicated that a variety of unrelated motility disorders of the GI tract may be linked to improper development of lCC or loss of ICC in mature tissues. The underlying causes for compromised Kit signaling and loss of ICC in patients have led to the development of several animal models where changes in ICC networks can be systematically investigated. Using a combination of morphological and physiological approaches together with organotypic cultures and murine animal models that mimic human disorders, the importance of Kit signaling for the development and maintenance of lCC networks will be investigated in this proposal. Specific questions will examine: (A) the importance of the Kit signaling pathway for ICC development prior to and after birth (ii) the phenotypic plasticity of ICC during and after development and (iii) how ICC networks are affected under pathophysiological conditions that alter GI motility and are ICC capable of repopulating tissues after removal of pathophysiological insults. Information obtained from this proposal may provide insight into the mechanisms leading to the loss of these cells and associated motility disorders in humans.

从胃肠道不同区域分离的组织表现出自发的电和机械活动。当同时记录收缩和膜电位时，每次收缩都会由持久的去极化波（称为慢波）触发。慢波活动产生的起源和基础多年来一直争论不休，但现在人们普遍认为这些起搏器电位来自一组单独的细胞，称为卡哈尔间质细胞 (ICC)。大多数平滑肌细胞的机械活动也受到自主神经或肠神经的调节。以前人们认为平滑肌中的神经传递是通过简单扩散发生的。然而，神经末梢似乎并不直接与平滑肌细胞沟通，而是与胃肠道多个区域的 ICC 形成密切的突触关系。这些接触对于胃肠道肌肉协调运动神经传递是必要的。运动障碍传统上被定性为肌病性或神经病性起源，尽管大多数患有这些疾病的患者在活检中肠神经或平滑肌细胞并未表现出明显的组织病理学变化。 ICC 表达受体酪氨酸激酶 Kit 的发现为病理学家和胃肠病学家提供了一种方法来了解先天性或获得性运动障碍患者中发生的 ICC 变化。最近的几项临床研究表明，胃肠道的各种不相关的运动障碍可能与 lCC 发育不当或成熟组织中 ICC 的丧失有关。 Kit 信号传导受损和患者 ICC 丢失的根本原因导致了几种动物模型的开发，可以系统地研究 ICC 网络的变化。本提案将结合形态学和生理学方法以及模拟人类疾病的器官型培养物和鼠类动物模型，研究 Kit 信号传导对于 lCC 网络发育和维持的重要性。具体问题将检查：(A) Kit 信号通路对出生前后 ICC 发育的重要性 (ii) ICC 发育期间和之后的表型可塑性，以及 (iii) ICC 网络在改变胃肠道运动的病理生理条件下如何受到影响，以及 ICC 是否能够在去除病理生理损伤后重新填充组织。从该提案中获得的信息可能有助于深入了解导致人类这些细胞丧失和相关运动障碍的机制。