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

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.