Development and plasticity of ICC

ICC的发展与可塑性

• 批准号: 6801332
• 负责人: Sean M Ward
• 金额: $ 17.39万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801332
• 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显示自发的电和机械活动。当收缩和膜电位同时被记录下来时，每次收缩都由一个被称为慢波的持久去极化波触发。慢波活动产生的起源和基础已经争论了很多年，但现在被广泛接受的是，这些起搏器电位来自一组独立的细胞，称为Cajal间质细胞（ICC）。大多数平滑肌细胞的机械活动也被自主神经或肠神经所改变。以前，人们认为平滑肌中的神经传递是通过简单的扩散发生的。然而，神经末梢似乎不是直接与平滑肌细胞交流，而是在胃肠道的几个区域与ICC形成密切的突触关系。这些接触是协调胃肠道肌肉运动神经传递所必需的。运动障碍传统上被定性为肌病或神经病的起源，尽管大多数患有这些疾病的患者在活检中没有表现出明显的肠神经或平滑肌细胞的组织病理学改变。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ICC的变化。最近的几项临床研究表明，各种不相关的胃肠道运动障碍可能与lCC发育不当或成熟组织中ICC的缺失有关。Kit信号通路受损和患者ICC丢失的潜在原因导致了几种动物模型的发展，可以系统地研究ICC网络的变化。结合形态学和生理学方法，结合器官型培养和模拟人类疾病的小鼠动物模型，本提案将研究Kit信号传导对lCC网络发展和维持的重要性。具体问题将研究：(A) Kit信号通路对出生前和出生后ICC发育的重要性；（ii） ICC在发育期间和之后的表型可塑性；（iii） ICC网络如何在改变GI运动的病理生理条件下受到影响，以及ICC是否能够在去除病理生理损伤后重新填充组织。从这一建议中获得的信息可能为人类导致这些细胞丧失和相关运动障碍的机制提供见解。