Role for ion conducting proteins in cortical malformation diseases

候选人。在我的博士后培训中，我从基于神经生物学的老鼠感觉方法过渡到 加工(PHD)，到人类神经发育的分子和遗传方法。目前，差距很大。 存在于功能神经基因组学领域，因此临床衍生的基因组分析目前无法 被忠实地翻译成功能数据。我继续接受克里斯托弗·沃尔什博士研究的培训 小组将通过支持我在人类遗传学方面的新专业知识的开发来加强这一研究利基 和单细胞方法。此外，我的长期目标是发展评估基因如何 影响细胞兴奋性的物质(如通道、泵、交换器)可以指导神经回路的发育 与我的研究生培训相辅相成，在那里我发展了电子细胞基础的专业知识 嗅觉和小脑神经回路中的信号。特别是，我的研究生学习巩固了我的专业知识 在神经系统生理学和单个神经元对电路功能的贡献，包括全细胞贴片 钳夹电生理学、钙成像、光遗传学、化学遗传学和体内行为范例。这个 将这些技能应用于人类神经发育领域将成为开发我的 独立研究计划。 研究。离子通道可以破坏皮层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。自从将祖细胞和新生神经元分离到 发育中的大脑皮层依赖于离子来控制细胞过程，我将测试新的假设 特定离子通量的活性中断是皮层组装的关键。发展性的存在的证明 由于皮质畸形的异质性，大脑中的通道病变仍然难以捉摸。 事实上，他们经常在进化过程中承受着极端的负面压力。鉴于我所描述的 以及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)相关的条件，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对诊断为 精神错乱。我将结合经验证的和创新的策略来完成这项研究，包括： 1)对无血缘和有血缘关系的家系进行测序分析，以确定涉及的基因变异 脑部畸形；2)描述了一种新的发育经络病小鼠模型； 3)开发一种新的人脑器官发育的生理学检测方法。

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.