CRCNS: Transmitter Release Site Organization in Plasticity and Disease at the NMJ

CRCNS：NMJ 可塑性和疾病领域的发射机释放站点组织

• 批准号: 8837233
• 负责人: Thomas A Blanpied
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837233
• 关键词: Affect; Anatomy; Arts; Back; Behavior; Biological Models; Cell physiology; Cells; Collaborations; Communication; Communities; Community Outreach; Complex; Computational Biology; Computer Simulation; Disease; Docking; Doctor of Philosophy; Educational process of instructing; Educational workshop; Environment; Event; Faculty; Funding; High School Student; Housing; Image; Institution; K-12 Education; Knowledge; Laboratories; Lambert-Eaton Myasthenic Syndrome; Lead; Learning; Maryland; Mediating; Mentors; Mission; Modeling; Mus; Nerve; Nervous system structure; Neurologic; Neurons; Neurosciences; New Mexico; Online Systems; Participant; Pennsylvania; Physiology; Plant Roots; Play; Postdoctoral Fellow; Proteins; Rana; Research; Research Personnel; Resolution; Role; Schools; Science; Site; Source; Spatial Distribution; Structure; Students; Supercomputing; Synapses; Synaptic Transmission; Synaptic Vesicles; Teacher Professional Development; Teaching Materials; Testing; Training; Underrepresented Minority; Universities; Vesicle; Visit; Work; base; biomedical resource; career; chemical release; college; disorder control; high school; insight; member; movie; nervous system disorder; neuromuscular; neurotransmitter release; outreach; outreach program; postsynaptic; presynaptic; programs; research study; simulation; synaptic function; tool; undergraduate research; undergraduate student

DESCRIPTION (provided by applicant): Communication between cells in the nervous system underlies all complex behaviors, and occurs at specialized regions of the nerve cell called synapses. Synapses work by releasing chemical transmitter from a region called the active zone, which activates a neighboring cell. We propose to characterize the relationship between active zone function and structural organization within frog and mouse neuromuscular synapses. We hypothesize that neuromuscular active zones are assembled from a basic transmitter release building block: the unreliable single-vesicle release site consisting of a docked synaptic vesicle and its associated Ca2+ channels. We further hypothesize that major aspects of synaptic function and presynaptic homeostatic plasticity can be explained by changes in the number and organization of these single-vesicle release sites within active zones. Our approach is characterized by a seamless collaboration between three labs with expertise in computer simulations of cellular physiology (Dittrich lab), synaptic anatomy, physiology, and Ca2+ imaging (Meriney lab), and super-resolution imaging of the number and spatial distribution of synaptic proteins (Blanpied lab). Importantly, as part of this proposal, trainees from all three laboratories will receive crosstraining in each lab. We will use this collaborative approach to develop a comprehensive MCell computer model of the presynaptic transmitter release site that will significantly increase our understanding of the relationship between active zone organization and synaptic function. This insight will not only lead to a better understanding of presynaptic mechanisms of homeostatic plasticity but also aid in our understanding of synaptic diseases, which are known to underlie a large number of neurological disorders. Intellectual Merit: A significant number of neurological diseases are known to affect the synapse by targeting synaptic organization and function. While most research on this important topic has to date focused on postsynaptic adaptations, it has become increasingly clear that presynaptic homeostatic changes are likely to be just as important. Thus, a better understanding of the role of presynaptic structure and organization in synaptic function under both control and disease conditions is needed. Broader Impacts: The MCell model that we will develop will enhance our teaching mission in many ways. It will provide an example of unprecedented scale and realism for the illustration of nerve terminal structure and function. This material will be used in courses and programs at the University of Pittsburgh, the University of Maryland, and Carnegie Mellon University. These include undergraduate and graduate Neuroscience courses, a Computational Biology PhD program that spans PITT and Carnegie Mellon University, summer workshops, and web-based tutorials (www.mcell.org). These simulations will expand previous models that already have been converted into instructive 3D movies, which are routinely shown to a broad range of audiences during open houses, student visits or classroom teaching. This work will also provide source material for teaching examples tailored to high school outreach programs at the Pittsburgh Supercomputing Center, particularly the CMIST program (Computational Modules in Science Teaching, www.cmist.org) of the National Resource for Biomedical Supercomputing (NRBSC) directed by Dr. Dittrich. Our proposed work will have a broad impact on K-12 education, undergraduate teaching and training, graduate and post-graduate training, community outreach, STEM teaching, training at underrepresented minority institutions, and knowledge of synaptic function in the field. Dr. Meriney is a member of the Neuroscience outreach committee at the University of Pittsburgh (PITT), which organizes a variety of community events. Dr. Meriney's laboratory is in the Arts and Sciences College, so the proposed research would contribute to undergraduate teaching via undergraduate research participation in the proposed work, and changes to content for undergraduate courses based on new research insights. Dr. Dittrich will also train undergraduate students in his laboratory as participants in the proposed work. He is training faculty in the NSF funded TECBio REU program at the PITT and typically mentors 1-2 students in computational projects as part of the program. In addition, Dr. Dittrich is a training faculty in the PA Governors School for the Sciences, an intense summer program for talented high school students in Pennsylvania. Drs. Dittrich, Meriney, and Blanpied will bring graduate researchers and postdoctoral fellows into their labs who will directly participate in the proposed experiments, receive cross training in all three laboratories, and receive career training. Lastly, Dr. Ulises Ricoy (an under-represented minority faculty member) from Northern New Mexico College will visit during each summer to learn new research, teaching, and training tools to bring back to underrepresented minority undergraduates at Northern New Mexico College. This will expose these underrepresented minority students to an intense academic research environment and aid in their training and career planning.

描述（由申请人提供）：神经系统中细胞之间的通信是所有复杂行为的基础，并且发生在称为突触的神经细胞的专门区域。突触通过从称为活性区域的区域释放化学发射器来起作用，该区域激活相邻的细胞。我们建议表征青蛙和小鼠神经肌肉突触中的活动区功能与结构组织之间的关系。我们假设神经肌肉活性区是从基本的发射器释放构建块组装而成的：不可靠的单维释放位点由停靠的突触囊泡及其相关的Ca2+通道组成。我们进一步假设突触功能和突触前稳态可塑性的主要方面可以通过活动区域内这些单维释放位点的数量和组织的变化来解释。我们的方法的特征是在三个实验室之间进行了无缝的协作，在计算机生理学（Dittrich Lab）中具有专业知识（Dittrich Lab），突触解剖学，生理学和CA2+成像（Meriney Lab）（Meriney Lab），以及对突触蛋白的数量和空间分布的超分辨率成像（Blanpied Lab）。重要的是，作为该提案的一部分，来自所有三个实验室的学员都将在每个实验室接受交叉培训。我们将使用这种协作方法来开发突触前发射器发行站点的全面MCELL计算机模型，该模型将大大提高我们对活动区组织与突触功能之间关系的理解。这种见解不仅会带来更好的 了解稳态可塑性的突触前机制，同时也有助于我们对突触疾病的理解，这些疾病已知是大量神经系统疾病的基础。 智力优点：已知大量神经系统疾病通过靶向突触组织和功能来影响突触。尽管大多数关于这个重要主题的研究都集中在突触后适应上，但越来越明显的是，突触前的稳态变化可能同样重要。因此，需要更好地了解在控制和疾病条件下突触前结构和组织在突触功能中的作用。 更广泛的影响：我们将开发的MCELL模型将以许多方式增强我们的教学任务。它将为神经终端结构和功能的说明提供前所未有的规模和现实主义的示例。该材料将用于匹兹堡大学，马里兰大学和卡内基·梅隆大学的课程和课程。其中包括跨越皮特和卡内基·梅隆大学的计算生物学博士学位课程，夏季讲习班以及基于Web的教程（www.mcell.org）。这些模拟将扩大已经转换为有启发性的3D电影的先前模型，这些模型通常会在开放式房屋，学生访问或课堂教学期间通常向广泛的受众展示。这项工作还将为匹兹堡超级计算中心量身定制的教学示例提供材料，尤其是科学教学的CMIST计划（计算模块，www.cmist.org），www.cmist.org）由Dittrich博士指导的国家生物医学超级计算资源（NRBSC）。我们拟议的工作将对K-12教育，本科教学和培训，研究生和研究生培训，社区外展，STEM教学，代表性不足的少数族裔机构的培训以及该领域的突触功能知识。 Meriney博士是匹兹堡大学（PITT）神经科学外展委员会的成员，该委员会组织了各种社区活动。 Meriney博士的实验室是艺术与科学学院的实验室，因此拟议的研究将通过本科研究参与拟议的工作有助于本科教学，并根据新的研究见解的本科课程的内容变化。 Dittrich博士还将在实验室中培训本科生，担任拟议工作的参与者。他正在PITT培训NSF资助的Tecbio REU计划中的教职员工，通常在计算项目中指导1-2名学生，作为该计划的一部分。此外，Dittrich博士是PA Consors The Sciences的培训学院，这是一项针对宾夕法尼亚州才华横溢的高中生的激烈夏季计划。博士。 Dittrich，Meriney和Blanpied将将研究生研究人员和博士后研究员带入他们的实验室，他们将直接参加拟议的实验，并接受所有人的交叉培训 三个实验室，并接受职业培训。最后，来自新墨西哥州北部学院的Ulises Ricoy博士（一位代表性不足的少数群体教师）将在每个夏天访问，以学习新的研究，教学和培训工具，以带回新墨西哥北部北部代表性不足的少数族裔本科生。这将使这些代表性不足的少数族裔学生面临强烈的学术研究环境，并帮助他们的培训和职业计划。