Development and plasticity of Interstitial Cells of Cajal

卡哈尔间质细胞的发育和可塑性

• 批准号: 7413387
• 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: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413387
• 关键词: Affect; Animal Model; Apoptosis; Back; Biopsy; Birth; Cells; Clinical Research; Condition; Development; Diffusion; Disease; Disruption; Embryonic Development; Enteral; Excision; Gastroenterologist; Gastrointestinal Motility; Gastrointestinal tract structure; Generations; Human; Hypertrophy; Interstitial Cell of Cajal; Intestines; Lead; Link; Maintenance; Mechanics; Membrane Potentials; Modeling; Motor; Mus; Muscle; Nerve; Neuropathy; Obstruction; Pacemakers; Pathologist; Patients; Phenotype; Physiological; Postoperative Period; Principal Investigator; Receptor Protein-Tyrosine Kinases; Signal Pathway; Signal Transduction; Small Intestines; Smooth Muscle; Smooth Muscle Myocytes; Stem Cell Factor; Synapses; Thinking; Tissues; Transcriptional Activation; Up-Regulation; base; cell motility; embryo tissue; extracellular; insight; interstitial cell; motility disorder; muscle hypertrophy; neurotransmission; programs; receptor; relating to nervous system; response

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.

分离自胃肠道不同区域的组织显示出自发的电和机械活动。当同时记录收缩和膜电位时，每次收缩都是由一种持久的去极化波触发的，这种波被称为慢波。慢波活动的起源和基础多年来一直存在争议，但现在人们普遍认为这些起搏电位来自一组独立的细胞，即Cajal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的扩散发生的。然而，神经末梢似乎不是直接与平滑肌细胞通信，而是在胃肠道的几个区域与ICC形成密切的突触关系。这些接触是胃肠道肌肉协调运动神经传递所必需的。传统上，动力障碍的起源是肌病或神经性疾病，尽管大多数患有这些疾病的患者在活检中并没有表现出明显的肠神经或平滑肌细胞的组织病理学变化。随着ICC表达受体酪氨酸激酶的发现，Kit为病理学家和胃肠病学家提供了一种方法，可以了解先天性或获得性动力障碍患者的ICC变化。最近的一些临床研究表明，各种无关的胃肠道动力障碍可能与LCC的发育不当或成熟组织中ICC的丢失有关。Kit信号受损和患者ICC丢失的根本原因导致了几种动物模型的发展，在这些动物模型中，ICC网络的变化可以被系统地研究。结合形态学和生理学方法，结合器官类型培养和模拟人类疾病的小鼠动物模型，Kit信号对LCC网络的发展和维护的重要性将在本提案中进行研究。具体问题将检查：(A)Kit信号通路在出生前和出生后对ICC发育的重要性(Ii)ICC在发育过程中和之后的表型可塑性以及(Iii)ICC网络在改变胃肠道动力的病理生理条件下如何受到影响，以及ICC是否能够在移除病理生理损伤后重新填充组织。从这项建议中获得的信息可能会为深入了解导致这些细胞丢失的机制以及相关的人类运动障碍提供线索。