UC Irvine Center for the production and distribution of cell-type-specific viral targeting reagents

加州大学欧文分校细胞类型特异性病毒靶向试剂生产和分销中心

基本信息

批准号：
10664193
负责人：
GORDON J FISHELL
金额：
$ 166.12万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664193
关键词：
Aliquot Asian Americans Award BRAIN initiative Brain California Capsid Cells Cerebral cortex Charge Collaborations Communities Custom Dependovirus Development Enhancers Ensure Exclusion Faculty Funding Gene Delivery Gene Expression Genetic Goals Grant Hand Health Sciences Hispanic-serving Institution Human In Vitro Institution Interneurons Maps Minority-Serving Institution Modeling Molecular Monkeys Morehouse School of Medicine Mus Native Americans Neurons Neurosciences Pacific Island Americans Participant Production Qualifying Quality Control Reagent Recombinant adeno-associated virus (rAAV)Recovery Regulator Genes Regulatory Element Reporter Reproducibility Research Research Personnel Research Project Grants Resolution Resources Rodent Scientific Advances and Accomplishments Scientist Serotyping Services Students Technology Underrepresented Minority United States National Institutes of Health Universities Validation Viral Viral Vector Virus Work adeno-associated viral vector brain cell brain circuitry cell community cell type cost design designer receptors exclusively activated by designer drugs diversity and inclusion excitatory neuron experience improved in vivo inhibitory neuron member minority communities minority trainee neural circuit neurotropic virus nonhuman primate novel recruit response scale up screening tool underrepresented minority student vector virus genetics

项目摘要

Project Summary Gaining genetic access to specific cell types in rodents, non-human primates and other vertebrate species is critical for enabling targeted circuit manipulations to understand normal brain function and brain. The use of gene regulatory elements for targeted gene expression is transforming brain circuitry studies. In response to RFA-MH-21-180, the Center for Neural Circuit Mapping (CNCM) team led by Dr. Xiangmin Xu at the Minority Serving Institution (MSI)-designated institution, University of California, Irvine (UCI) will collaborate with Dr. Gordon Fishell’s team at Harvard University and the Broad Institute to produce and distribute reagents developed by their Armamentarium project, “Systematic identification of enhancers to target the breadth of excitatory and inhibitory neuronal cell types in the cerebral cortex” (U01MH13070, pending award). Dr. Fishell’s team has established a novel high-throughput enhancer screening platform using gene regulatory elements that enables cell type-restricted gene expression in cortical GABAergic interneuron and pyramidal excitatory neuron subtypes at an unprecedented resolution. This is achieved using adeno-associated virus (AAV) vectors for the effective screening and validation of enhancers for specific neuron types in the mouse, non-human primate, and human brain. The first goal of our proposed research is to establish close collaborations between the UCI and Harvard University/Broad Institute teams to scale up and optimize the production of cell-type-specific enhancer-AAVs. Using our growing Center platform, the UCI team will distribute these viral reagents to qualified investigators in the neuroscience community for cell-type-specific access and manipulation. The second goal of our research is to enhance the impact of this project by engaging scientists and students from diverse backgrounds and less research-intensive institutions that serve minority communities. In Aim 1, the UCI team will form a partnership with Dr. Fishell’s team to expand seed enhancer-AAV reagents characterized by Dr. Fishell’s team to make a broad set of tools for cell-type-specific neural circuit studies across vertebrate species. We will leverage our CNCM existing expertise in neurotropic virus production and distribution to make new helper AAVs based on Dr. Fishell’s enhancers to improve the precision of genetically targeted specific circuit mapping in the CNS. In Aims 2 and 3, we will coordinate with Dr. Fishell’s pilot U01 project investigators to scale up our UCI CNCM viral production pipeline and improve our distribution platform to support viral reagent production, validation, and ample supplies for research community distribution. We will expand our recruitment of team members from diverse backgrounds facilitated by partnering with Western University of Health Sciences and Morehouse School of Medicine to include faculty, staff and students of underrepresented minorities for the proposed research. We will fulfill the RFA requirement to generate and distribute authenticated viral reagents in a well-regulated manner to be widely used in the research community. This U24 award will provide critical support for the BRAIN-Initiative Armamentarium project.

项目摘要在啮齿动物，非人类灵长类动物和其他脊椎动物中获得遗传获取的遗传获取是对于使靶向电路操作能够理解正常的大脑功能和大脑至关重要。使用针对靶向基因表达的基因调节元素正在转化脑回路研究。响应 RFA-MH-21-180，由Xiangmin Xu博士领导的神经电路映射中心（CNCM）团队加利福尼亚大学尔湾分校（UCI）服务机构（MSI）指定的机构将与博士合作哈佛大学的戈登·费舍尔（Gordon Fishell）的团队和开发生产和分发试剂的广泛研究所通过他们的Armammentarium项目，“对增强子的系统识别，以针对兴奋性和大脑皮层中的抑制性神经元细胞类型”（U01MH13070，待定奖）。费舍尔博士的团队有使用基因调节元素建立了一种新型的高通量增强子筛选平台细胞类型限制的基因表达在皮质GABA能中间神经元和锥体兴奋性神经元亚型中以前所未有的决议。这是使用腺相关病毒（AAV）向量来实现的筛选和验证小鼠，非人类灵长类动物和人类特定神经类型的增强子脑。我们拟议的研究的第一个目标是建立UCI和哈佛之间的密切合作大学/广泛的研究所团队将扩大和优化细胞类型的增强剂-AAVS的生产。 UCI团队使用我们不断增长的中心平台将这些病毒试剂分发给合格的调查人员用于细胞类型的特定访问和操纵的神经科学界。我们研究的第二个目标是通过吸引来自潜水员背景的科学家和学生来增强该项目的影响为少数民族社区服务的研究密集型机构。在AIM 1中，UCI团队将建立合作伙伴关系 Fishell博士的团队以Fishell博士的团队为特征，以扩大种子增强剂-AAV试剂跨脊椎动物物种的细胞类型特异性神经元回路研究的广泛工具。我们将利用我们的 CNCM神经性病毒生产和分发方面的现有专业知识，以根据Dr. Fishell的增强剂提高了中枢神经系统中一般针对特定电路映射的精度。在目标中 2和3，我们将与Fishell博士的Pilot U01项目调查人员进行协调，以扩大我们的UCI CNCM病毒生产管道并改善我们的分销平台，以支持病毒试剂生产，验证和研究社区分布的充足供应。我们将从团队成员的招聘中扩大通过与西方健康科学大学和莫尔豪斯学校合作准备的潜水背景拟议研究的医学包括教职员工，教职员工和代表性不足的少数群体的学生。我们将满足RFA以良好调节的方式生成和分发认证的病毒试剂的要求在研究社区中广泛使用。该U24奖将为大脑发射提供重要的支持 Armamentarium项目。