# Large scale discovery and validation of brain cell type enhancers for viral targeting and circuit manipulation

> **NIH NIH RF1** · DUKE UNIVERSITY · 2020 · $3,931,308

## Abstract

Abstract – No change from original application
Brain functions emerge from highly nuanced spatiotemporal dynamics of neural circuit computation
mediated by diverse and precisely interconnected neuron types. Specific and systematic experimental access
to these cell types are prerequisites to deciphering brain circuit organization and function, but this has been a
prohibitive bottleneck in neuroscience. Although powerful, current genetic approaches in mammals are mostly
restricted to germline engineering in the mouse and have fundamental limitations in time, cost, scale, versatility
and clinical application. What is urgently needed is the ability to identify and manipulate cell types in a way
that is: 1) specific (to bona fide types defined by anatomical and physiological properties), 2)
comprehensive (to many cell types), 3) fast (days instead of months to years), 4) inexpensive, and 5) across
mammalian species. We propose to develop a paradigm-shifting platform that will enable rapid and
comprehensive access for brain cell types across mammalian species by leveraging fundamental epigenomic
and gene regulatory basis of cell types - the transcriptional enhancers. We will establish a cellular resolution
and scalable pipeline for identifying cell type enhancers in the mouse brain that combines 1) chromatin
landscape analysis (ATAC-seq) in genetic driver-defined neuronal subpopulations, 2) innovative AAV- and
sequencing-based massively parallel reporter assays in these subpopulations, 3) high-throughput validation
using a novel method of integrated spatial transcriptomics and sequencing-based projection mapping, and
4) high-resolution whole brain morphological imaging. We aim for comprehensive coverage of neuron types
of the cerebral cortex, including both glutamatergic pyramidal neurons and GABAergic interneurons, though
our strategy and tools will be general to other brain regions and species. The Huang lab has systematically
generated combinatorial genetic driver lines targeting major cortical neuron subpopulations and has discovered
the transcriptional basis of cortical neuron types. Bing Ren is a leader in enhancer biology and has pioneered
the technical advances in cell type and single cell chromatin analysis, including computational approaches.
Tony Zador invented MAPseq, BARseq and other sequencing-based methods that enable high throughput,
cellular resolution mapping of neuronal connectivity. Pavel Osten has pioneered developing high-resolution
and high-throughput whole brain imaging pipelines with associated computational analysis. Together, our
knowledge and expertise constitute a synergistic team focusing on an excellent experimental system for the
systematic screening, discovery and validation of cell type enhancers and for generating cell census datasets
that contribute to the BICCN goals. Our approach is grounded in fundamental genetic principles and
mechanisms and has the potential to transform the scale and rate of discovery across ne...

## Key facts

- **NIH application ID:** 10327151
- **Project number:** 7RF1MH124612-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Yarui Diao
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,931,308
- **Award type:** 7
- **Project period:** 2020-09-23 → 2023-09-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327151

## Citation

> US National Institutes of Health, RePORTER application 10327151, Large scale discovery and validation of brain cell type enhancers for viral targeting and circuit manipulation (7RF1MH124612-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10327151. Licensed CC0.

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