Role for ion conducting proteins in cortical malformation diseases

离子传导蛋白在皮质畸形疾病中的作用

• 批准号: 10619098
• 负责人: Richard S Smith
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619098
• 关键词: Role; ion; conducting; proteins; cortical

Candidate. For my postdoctoral training, I transitioned from neurobiology-based methods in mouse sensory processing (PhD), to molecular and genetic approaches in human neurodevelopment. At present, a large gap exists in the field of functional neurogenomics, whereby clinically-derived genomic analysis is currently unable to be faithfully translated into functional data. My continued training with Dr. Christopher Walsh's research group will build into this research niche by supporting my development of new expertise in human genetics and single-cell approaches. Further, my long-term goal is to develop the broad skills needed to assess how genes that affect cellular excitability (e.g. channels, pumps, exchangers) can instruct neural circuit development; this complements well with my graduate training, where I developed expertise in the cellular basis of electrical signaling in olfactory and cerebellar neural circuits. In particular, my graduate studies cemented my expertise in neural systems physiology and single neuron contributions to circuit function, including whole-cell patch clamp electrophysiology, calcium imaging, optogenetics, chemogenetics, and in-vivo behavioral paradigms. The application of these skills to the area of human neurodevelopment will form the basis for developing my independent research program. Research. The idea that ion channels can disrupt cortex formation is a new area of study, particularly when exploring the mechanisms activated at a cellular level. Since dividing progenitor cells and newborn neurons in the developing cerebral cortex rely on ions for controlling cellular processes, I will test the new hypothesis that disrupted activity of specific ion fluxes is critical to cortex assembly. Proof of the existence of developmental channelopathies in the brain has remained elusive due to the heterogenous nature of cortical malformations and the fact that they are often are under extreme negative pressure evolutionarily. Given that I am describing and categorizing brain disorders that improve our understanding of disease mechanisms and the treatment of conditions related to malformation of cortical development (MCD), the significance of this work to human health is immediate as the results generated by this research will immediately improve genetic testing for diagnosed disorders. I will complete this research with a combination of both proven and innovative strategies, including: 1) sequencing analysis of non-consanguineous and consanguineous families to identify gene variants involved in brain malformations; 2) characterizing a novel mouse model for a developmental channelopathy; 3) development of a novel physiological assay in developing human cerebral organoids.

候选人。在我的博士后培训中，我从基于神经生物学的小鼠感觉方法转变为 处理（博士），人类神经发育的分子和遗传方法。目前差距较大 存在于功能神经基因组学领域，目前无法进行临床衍生的基因组分析 忠实地转化为功能数据。我继续接受克里斯托弗·沃尔什博士研究的培训 小组将通过支持我发展人类遗传学新专业知识来建立这一研究领域 和单细胞方法。此外，我的长期目标是培养评估基因如何发挥作用所需的广泛技能。 影响细胞兴奋性的因素（例如通道、泵、交换器）可以指导神经回路的发育；这 与我的研究生培训相得益彰，我在研究生培训中发展了电气细胞基础方面的专业知识 嗅觉和小脑神经回路中的信号传导。特别是，我的研究生学习巩固了我的专业知识 神经系统生理学和单个神经元对电路功能的贡献，包括全细胞补丁 钳电生理学、钙成像、光遗传学、化学遗传学和体内行为范式。这 将这些技能应用于人类神经发育领域将为我的发展奠定基础 独立研究计划。 研究。离子通道可以破坏皮质形成的想法是一个新的研究领域，特别是当 探索在细胞水平上激活的机制。由于祖细胞和新生神经元的分裂 发育中的大脑皮层依赖离子来控制细胞过程，我将测试这个新假设： 特定离子流的活动被破坏对于皮层的组装至关重要。发展存在性的证明 由于皮质畸形的异质性，大脑中的通道病仍然难以捉摸 事实上，它们在进化上常常处于极端的负压之下。鉴于我正在描述 对大脑疾病进行分类，以提高我们对疾病机制和治疗的理解 与皮质发育畸形（MCD）相关的病症，这项工作对人类健康的意义 是立竿见影的，因为这项研究产生的结果将立即改善诊断的基因检测 失调。我将结合经过验证和创新的策略来完成这项研究，包括： 1) 对非近亲和近亲家庭进行测序分析，以确定涉及的基因变异 脑部畸形； 2) 表征发育性通道病的新型小鼠模型； 3）开发一种新的生理检测方法来开发人类大脑类器官。