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: 9805867
• 负责人: Richard S Smith
• 金额: $ 9.21万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805867
• 关键词: 3-Dimensional; Affect; Area; Behavioral Paradigm; Benchmarking; Biological Assay; Brain; Brain Diseases; Calcium; Candidate Disease Gene; Cell physiology; Cells; Cerebral Palsy; Cerebral cortex; Cerebrum; Clinical; Clinical Data; Complement; Cortical Malformation; Coupled; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Effectiveness; Electrophysiology (science); Embryonic Development; Epilepsy; Fetal Development; Functional disorder; Future; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic Engineering; Genetic screening method; Genomics; Goals; Health; Heterogeneity; Homeostasis; Human; Human Genetics; Image; Immunohistochemistry; In Situ; In Vitro; Individual; Intellectual functioning disability; Ion Channel; Ions; Methods; Microgyria; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutate; Mutation; Nature; Neurobiology; Neurons; Organoids; Output; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Physiological; Physiology; Plant Roots; Play; Population; Proteins; Publishing; Pump; Research; Role; Sensory; Signal Transduction; Sodium Channel; Speech; Stem cells; System; Testing; Training; Transgenic Organisms; Translating; Variant; Work; base; brain malformation; cohort; consanguineous family; developmental disease; disease phenotype; exome sequencing; fetal; gain of function; genetic analysis; genetic approach; genetic disorder diagnosis; genetic variant; human model; improved; in utero; in vitro Model; in vivo; induced pluripotent stem cell; innovation; malformation; malformation in cortical development; migration; model development; mouse model; nervous system disorder; neural circuit; neurodevelopment; neurogenomics; neurophysiology; newborn neuron; novel; novel strategies; optogenetics; patch clamp; post-doctoral training; pressure; proband; progenitor; programs; relating to nervous system; segregation; single-cell RNA sequencing; skills; sodium ion; transcriptomics; voltage

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， 处理（博士学位），在人类神经发育的分子和遗传方法。目前， 存在于功能性神经基因组学领域，由此临床衍生的基因组分析目前不能 将其忠实地转换为功能数据。我继续接受克里斯托弗沃尔什博士的研究训练 通过支持我在人类遗传学方面的新专业知识的发展， 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人类健康所需的广泛技能。 影响细胞兴奋性（如通道，泵，交换器）可以指导神经回路的发展;这 这与我的研究生训练很好地互补，在那里我发展了电的细胞基础方面的专业知识。 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，包括全细胞补丁 钳位电生理学、钙成像、光遗传学、化学遗传学和体内行为范例。的 将这些技能应用于人类神经发育领域将成为发展我的基础 独立研究计划。 Research.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 探索在细胞水平激活的机制。自从分裂祖细胞和新生神经元以来， 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， 特定离子流的中断活动对于皮层组装是关键的。证明发展的存在 由于皮质畸形的异质性， 事实上，它们在进化过程中经常处于极端的负压下。鉴于我描述的是 以及对大脑疾病进行分类，以提高我们对疾病机制和治疗方法的理解。 皮质发育畸形（MCD）的相关条件，这项工作对人类健康的意义 这项研究产生的结果将立即改善诊断的基因检测， 紊乱我将结合经过验证和创新的策略来完成这项研究，包括： 1)对非血亲和血亲家庭进行测序分析，以确定涉及的基因变异 2）表征发育性通道病的新型小鼠模型; 3)开发了一种新的发育人脑类器官的生理测定法。