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Novel Mechanism of Induction of Eye Tissue: Katp Channel Modulation

眼组织诱导的新机制：Katp 通道调制

基本信息

批准号：
7906653
负责人：
MICHAEL LEVIN
金额：
$ 33.72万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906653
关键词：
3-Dimensional Aging Animal Model Anterior Area Biochemical Biological Models Biology Biophysics Cell Cycle Progression Cell Fate Control Cell membrane Cells Complement Complex Congenital Abnormality Data Defect Degenerative Disorder Developmental Biology Developmental Cell Biology Diabetes Mellitus Dominant-Negative Mutation Electrophysiology (science)Embryo Embryonic Development Employee Strikes Endoplasmic Reticulum Event Eye Eye Development Foundations Generations Genes Genetic Genomics Goals Growth Human In Vitro Injury Institutes Ion Channel Ions Learning Left Light Link Location Mammals Medical Membrane Messenger RNA Metabolism Mission Modeling Molecular Molecular Biology Molecular and Cellular Biology Morphogenesis Natural regeneration Organ Pathway interactions Pattern Pattern Formation Pharmacologic Substance Phenotype Physiology Potassium Channel Process Production Property Proteomics Pump Rana Reagent Regulation Research Retina Role Science Scientist Side Signal Transduction Somatic Cell Systems Biology Tail Techniques Testing Therapeutic Tissues Training Translating Transplantation Visual system structure Work Xenopus Xenopus laevis cancer stem cell cell motility clinically relevant disorder control fascinate in vivo insight interest lens loss of function migration neural patterning novel prevent relating to nervous system repaired research study tool voltage

项目摘要

DESCRIPTION (provided by applicant): Important biomedical applications, as well as advances in basic biology, require a detailed understanding of pattern formation in embryonic development. In contrast and complement to the current focus on biochemical control factors, our lab seeks to understand and learn to manipulate evolutionarily-conserved endogenous static membrane voltage gradients and ion fluxes which control cell fate and morphogenesis. During experiments on the role of K+ fluxes in embryonic development, we discovered that specific modulation of the activity of Katp channels (K+ channels with crucial roles in metabolism, diabetes, and cardioprotection) induces ectopic eye tissue in frog embryos. The phenotypes range from isolated retina tissue and lenses, to complete eyes formed in many ectopic locations (including on the gut and tail). This is a very exciting finding because it 1) identifies a novel patterning role for an ion channel of high biomedical relevance, 2) reveals a molecular entrypoint into a completely novel aspect of eye development that may cause revisions of current models of eye induction, and 3) provides a new way to control cell fate (via modulation of K+ flux) in somatic cells, which has applications in the production of eye tissue in therapeutic applications. We propose to make breakthroughs in this important and highly novel area through a unique convergence in our lab of molecular biology, biophysics, and functional physiology techniques in a number of tractable model systems such as Xenopus laevis. Through five aims that use established techniques and reagents to test molecular hypotheses about the mechanisms of ectopic eye induction, we will understand the interaction of this event with the endogenous eye-forming pathways, discover exactly when, where, and how the ectopic eyes are induced, determine whether the ectopic eyes are functional, and identify novel genes linking Katp activity to the eye gene cascade.This work has high relevance to the AED and the missions of the Eye and General Medical Sciences Institutes because we propose to utilize powerful techniques in a tractable model animal to produce wide-reaching and important biomedical advances in understanding, preventing, and repairing birth defects and degenerative diseases of the visual system.

描述（由申请人提供）：重要的生物医学应用，以及基础生物学的进步，需要详细了解胚胎发育中的模式形成。与目前对生物化学控制因素的关注形成对比和补充，我们的实验室寻求理解和学习操纵进化保守的内源性静态膜电压梯度和离子通量，它们控制细胞的命运和形态发生。在关于K+通量在胚胎发育中的作用的实验中，我们发现对Katp通道（K+通道在代谢、糖尿病和心脏保护中起关键作用）活性的特异性调节可诱导青蛙胚胎的异位眼组织。表型范围从孤立的视网膜组织和晶状体，到在许多异位位置（包括肠道和尾巴）形成的完整眼睛。这是一个非常令人兴奋的发现，因为它1)确定了一个具有高度生物医学相关性的离子通道的新模式作用，2)揭示了一个进入眼睛发育全新方面的分子切入点，可能会导致当前眼睛诱导模型的修订，3)提供了一种控制体细胞细胞命运的新方法（通过K+通量的调节），这在眼组织的生产和治疗应用中有应用。我们建议通过分子生物学，生物物理学和功能生理学技术在一些可处理的模型系统（如非洲爪蟾）的实验室的独特融合，在这一重要而高度新颖的领域取得突破。通过使用已建立的技术和试剂来测试异位眼诱导机制的分子假设的五个目标，我们将了解这一事件与内源性眼睛形成途径的相互作用，准确地发现异位眼是何时、何地以及如何诱导的，确定异位眼是否具有功能，并确定将Katp活性与眼睛基因级联联系起来的新基因。这项工作与AED以及眼科和普通医学科学研究所的任务高度相关，因为我们建议在可驯化的模型动物中利用强大的技术，在理解、预防和修复视觉系统的出生缺陷和退行性疾病方面产生广泛而重要的生物医学进展。