EFRI-CBE: An Integrated Computational and Experimental Model for Biochemical and Electrical Interactions in Ion Channels and the Impact of Sialic Acid on Neuronal Function

PI名称：M.J.Betenbaugh研究所：约翰霍普金斯大学提案编号：0736000 EFRI-CBE：离子通道中生化和电相互作用以及唾液酸对神经元功能影响的集成计算和实验模型这个跨学科的项目汇集了五名互补的计算和实验研究人员，以建立一个集成的实验分析，可以破译外部环境的变化是如何以模型损伤(糖基化位点上的唾液酸丢失)的形式表现在钾通道的电特性变化中，最终导致携带这种缺陷的果蝇生物的瘫痪行为。唾液酸被选择来代表一种模型外部生化刺激，但这种生化修饰的确切生理作用仍然是一个相对鲜为人知的领域，特别是在神经元和活体动物模型中。为了了解唾液酸AICD的影响，首席调查员(PI)将利用分子尺度动力学模拟；创建与分子尺度动力学相关联的动力学和电生理特性的马尔可夫模型；并将这些预测与不同K-Shaker家族离子通道的实验细胞培养系统进行比较。该项目将比较分子模拟、马尔可夫模型和细胞培养系统预测的神经行为与唾液酸基因缺失的果蝇突变体的电生理和行为表型。了解生化环境和特别是唾液酸对电学性质和细胞动力学的作用，将有助于确定缓解症状的可能方法，并将测试潜在的药理脂质制剂以挽救或最大限度地减少缺陷。该项目将创建一个新的跨学科网络，由具有分子建模、离子通道建模、电生理学、生化工程和果蝇遗传学专业知识的研究人员组成，以调查生化环境，特别是糖基化和唾液酸对离子通道、神经过程和神经疾病的电特性和功能所起的作用。该小组来自不同的地理机构和不同的种族背景，其中两名联合教授S是女性。该计划将通过与城市学校的教师建立教育合作伙伴关系，让来自代表性不足群体的高中生和中学生更多地参与到大脑和脑部疾病的建模中。这个项目将通过展示如何利用苍蝇等实验系统来模拟和研究最复杂器官大脑的行为和疾病，让从初中、高中到研究生和博士后的学生们对工程学和科学的整合感到兴奋。

PI name: M.J. Betenbaugh Institution: Johns Hopkins University Proposal Number: 0736000 EFRI-CBE: An Integrated Computational and Experimental Model for Biochemical and Electrical Interactions in Ion Channels and the Impact of Sialic Acid on Neuronal Function AbstractThis interdisciplinary project brings together five complementary computational and experimental researchers to build an integrated and experimental analysis that can decipher how a change in the external environment in the form of a model insult (loss of sialic acid on a glycosylation site) is manifested in changes in the electrical properties of potassium channels that ultimately leads to paralytic behaviors in Drosophila organisms carrying this defect. Sialic acid was chosen to represent a model external biochemical stimulus, but the exact physiological role of this biochemical modification remains a relative poorly understood area especially in neuronal and in vivo animal models. To understand the effect of sialic aicd, the Principal Investigators (PIs) will utilize molecular scale dynamics simulations; create a Markov model of the kinetic and electrophysiological properties which connects to the molecular scale dynamics; and compare these predictions to experimental cell culture systems for different potassium Shaker family ion channels. This project will compare the neural behaviors predicted from molecular simulation, Markov models, and cell culture system to electrophysiology and behavior phenotypes of a Drosophila mutant in which the sialic acid gene is deleted. Understanding the role of the biochemical environment and particular sialic acid on electrical properties and cell dynamics will help one to identify possible methodologies for alleviating the symptoms, and potential pharmacological lipid agents to rescue or minimize the defect will be tested. This project will create a new interdisciplinary network of researchers with expertise in molecular modeling; ion channel modeling; electrophysiology, biochemical engineering, and Drosophila genetics to investigate the role that the biochemical environment, and in particular glycosylation and sialic acid, plays on electrical properties and function of ion channels, neuronal processes, and neurological disease. The group is drawn from a variety of different geographic institutions and diverse ethnic backgrounds, and two of the co-PI''s are female. The proposal will broaden the participation of high school and middle school students from underrepresented groups through an educational partnership with city school teachers in modeling the brain and brain disease. This program will excite students all the way from middle school and high school to graduate and post-doctoral levels about the integration of engineering and science by showing how behaviors and disease of the most complex organ, the brain, can be modeled and examined using experimental systems such as flies.