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。对于我的博士后培训，我从基于神经生物学的方法过渡了鼠标感觉的方法 处理（PHD），用于人类神经发育中的分子和遗传方法。目前，一个很大的差距 存在于功能性神经基础学领域，目前无法进行临床衍生的基因组分析 忠实地翻译成功能数据。我继续与克里斯托弗·沃尔什（Christopher Walsh）的研究进行培训 小组将通过支持我在人类遗传学方面的新专业知识来建立这一研究的利基市场 和单细胞方法。此外，我的长期目标是发展评估基因的广泛技能 影响细胞兴奋性（例如通道，泵，交换器）可以指导神经回路的发展；这 对我的研究生培训很好地补充，在那里我在电池的细胞基础上发展了专业知识 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 在神经系统生理学和对电路功能的单个神经元的贡献中，包括全细胞贴片 夹具电生理学，钙成像，光遗传学，化学遗传学和体内行为范式。这 这些技能在人类神经发育领域的应用将成为发展我的基础 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，尤其是 探索在细胞水平上激活的机制。由于将祖细胞和新生神经元分开 发育中的大脑皮层依赖于离子控制细胞过程，我将测试新的假设，即 特定离子通量的破坏活性对于皮层组件至关重要。发展的证据 由于皮质畸形的异质性质，大脑中的通道病仍然难以捉摸 而且它们通常在进化上处于极端负压下。鉴于我正在描述 并对脑部疾病进行分类，以提高我们对疾病机制的理解和治疗 与皮质发展（MCD）畸形有关的条件，这项工作对人类健康的重要性 立即是直接的，因为这项研究产生的结果将立即改善诊断的基因检测 疾病。我将结合经过验证和创新策略的结合完成这项研究，包括： 1）对非语言和血统家族的测序分析，以鉴定涉及的基因变异 在大脑畸形中； 2）表征开发通道病的新型小鼠模型； 3）开发一种新的生理测定法，以开发人类脑器官。