microRNAs targeting Kit inhibit the development and maintenance of ICC

microRNAs 靶向试剂盒抑制 ICC 的发展和维持

• 批准号: 8096488
• 负责人: Seungil Ro
• 金额: $ 21.15万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096488
• 关键词: Address; Animal Model; Apoptosis; Applications Grants; Bioinformatics; Cell Proliferation; Constipation; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Diarrhea; Endothelial Cells; Erythropoiesis; Fecal Incontinence; Fluorescence-Activated Cell Sorting; Functional disorder; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal tract structure; Genetic; Green Fluorescent Proteins; Growth; Human; Interstitial Cell of Cajal; Lead; Link; Maintenance; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Motor Neurons; Mus; Mutant Strains Mice; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Play; Principal Investigator; Proto-Oncogene Protein c-kit; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Sorting - Cell Movement; Stomach; Surface; Testing; Therapeutic; Translations; angiogenesis; cell motility; diabetic; gastrointestinal; gastrointestinal symptom; genetic regulatory protein; motility disorder; motor disorder; nodal myocyte; novel; programs

DESCRIPTION (provided by applicant): Interstitial cells of Cajal (ICC) are pacemaker cells that generate spontaneous electrical slow waves, and mediate inputs from motor neurons in the gastrointestinal (GI) tract. Loss or defects in ICC networks are directly linked to GI motility disorders. Recent studies have demonstrated that ICC plays an important role in the development of diabetic gastroenteropathy (DGEP). Patients with DGEP show loss or defects in ICC networks that may lead to GI motility disorders. ICC express the receptor tyrosine kinase, KIT, which is the receptor for stem cell factor. KIT signaling is required for the normal development and maintenance of ICC in the GI tract. Therefore, it is possible that loss of ICC in DGEP may be a result of reduced expression of KIT. Recent studies show that expression of Kit is regulated by microRNAs (miRNAs). Thus, our central hypothesis is that miRNAs targeting Kit inhibit the development and maintenance of ICC in DGEP. To address the hypothesis, we propose the following specific aims: 1) Characterization of microRNAome in ICC, 2) Identification of changes in microRNAs during the development of DGEP, and 3) Suppression of the growth and maintenance of ICC by miRNAs targeting Kit. To achieve the specific aims, we will utilize two animal models Kit+/copGFP and type 2 diabetic Kit+/copGFP;Lepob/ob mutant mice that we have recently generated . Both mice express a bright green fluorescent protein copGFP in a Kit-specific manner, which offers a powerful new model to study the function and genetic regulation of ICC phenotypes. Completion of the specific aims of this project will provide information about the miRNAs expressed specifically by ICC and how this body of regulatory molecules is altered in a major GI motor disorder. Our preliminary data suggest that many of the miRNAs in ICC target Kit. This study will describe a novel molecular mechanism involving miRNAs that inhibit KIT expression. This is an exciting opportunity to understand how KIT expression in ICC is regulated and how ICC are lost during the development of DGEP. Identification of the miRNAs inhibiting KIT expression may aid in the development of a therapeutic antisense miRNA drug that might be useful in blocking or reversing damaged ICC networks in DGEP and other GI motility and functional disorders in which loss of ICC occurs. PUBLIC HEALTH RELEVANCE: Loss of interstitial cells of Cajal (ICC) is directly linked to diabetic gastroenteropathy (DGEP), but the molecular mechanism underlying the ICC disruption is elusive. The present study seeks to uncover a novel mechanism involving microRNAs that lead to the loss of ICC during the development of DGEP.

描述（由申请人提供）：Cajal间质细胞（ICC）是产生自发电慢波的起搏细胞，并介导来自胃肠道（GI）运动神经元的输入。ICC网络的缺失或缺陷与GI动力障碍直接相关。近年来的研究表明，ICC在糖尿病胃肠病（DGEP）的发生发展中起着重要作用。DGEP患者表现出ICC网络的缺失或缺陷，可能导致GI动力障碍。ICC表达酪氨酸激酶受体KIT，KIT是干细胞因子的受体。KIT信号传导是胃肠道ICC正常发育和维持所必需的。因此，DGEP中ICC的丢失可能是KIT表达减少的结果。最近的研究表明Kit的表达受microRNA（miRNAs）的调控。因此，我们的中心假设是靶向Kit的miRNA抑制DGEP中ICC的发展和维持。为了解决这一假设，我们提出了以下具体目标：1）ICC中microRNAome的表征，2）DGEP发展过程中microRNA的变化，以及3）通过miRNA靶向试剂盒抑制ICC的生长和维持。为了实现特定的目标，我们将利用我们最近产生的两种动物模型Kit+/copGFP和2型糖尿病Kit+/copGFP;Lepob/ob突变小鼠。这两种小鼠表达明亮的绿色荧光蛋白copGFP的试剂盒特异性的方式，这提供了一个强大的新模型来研究ICC表型的功能和遗传调控。该项目的具体目标的完成将提供有关ICC特异性表达的miRNAs的信息，以及这种调节分子在重大GI运动障碍中如何改变。我们的初步数据表明，ICC中的许多miRNAs靶向Kit。这项研究将描述一种新的分子机制，涉及miRNA抑制KIT表达。这是一个令人兴奋的机会，以了解如何在ICC的KIT表达的调节和ICC是如何在DGEP的发展过程中丢失。抑制KIT表达的miRNA的鉴定可能有助于开发治疗性反义miRNA药物，该药物可能用于阻断或逆转DGEP和其他GI运动性和功能性疾病中受损的ICC网络，其中发生ICC损失。 公共卫生相关性：Cajal间质细胞（ICC）的丢失与糖尿病胃肠病（DGEP）直接相关，但ICC破坏的分子机制尚不清楚。本研究旨在揭示一种涉及microRNA的新机制，该机制导致DGEP发展过程中ICC的丢失。