Development and plasticity of ICC

ICC的发展与可塑性

基本信息

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
项目类别：
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

项目摘要

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.

从胃肠道的不同区域分离出来的组织显示自发的电和机械活性。当同时记录收缩和膜电位时，每次收缩都会由持续的去极化波触发，这些波动称为慢波。生成慢波活性的起源和基础已有很多年了，但现在已广泛认为这些起搏器电位来自一组单独的细胞，称为Cajal（ICC）的间质细胞（ICC）。大多数平滑肌细胞的机械活性也通过自主神经或肠神经来改变。以前据认为，平滑肌肉中的神经传递是通过简单扩散发生的。然而，看来神经末端，而不是与平滑肌细胞直接通信，而是在胃肠道的几个地区与ICC形成密切的突触关系。这些接触对于胃肠道肌肉中协调的运动神经传递是必需的。传统上，运动障碍的起源是肌病性或神经性疾病的特征，尽管大多数患有这些疾病的患者在活检中没有显示出明显的组织病理学变化或平滑肌细胞。 ICC表达受体酪氨酸激酶的发现，试剂盒为病理学家和胃肠病学家提供了一种访问先天性或熟悉运动障碍患者发生的ICC变化的方法。最近的一些临床研究表明，胃肠道的多种无关运动障碍可能与LCC的发展或成熟组织中ICC的丧失有关。患者的套件信号传导和ICC丢失的基本原因导致了几种动物模型的发展，在这些动物模型中，可以系统地研究ICC网络的变化。将使用形态学和生理方法以及模仿人类疾病的细胞型培养物和鼠类动物模型的结合，将在此提案中研究套件信号传导对LCC网络的开发和维持的重要性。具体问题将研究：（a）套件信号传导途径在出生前后的ICC发育的重要性（ii）ICC在开发过程中和发育过程中的表型可塑性以及（iii）ICC网络如何在病理生理状况下如何影响GI运动，并且能够改变ICC的ICC能够在病理生理学的重新生产后重新培养组织。从该提案中获得的信息可能会深入了解导致这些细胞丢失以及人类相关运动障碍的机制。