# Defining gene-by-environment interactions using multiplex single-cell genomics

> **NIH NIH R35** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2024 · $91,773

## Abstract

PROJECT SUMMARY
The proposed research program aims to develop systems for the multiplex assessment of the effect of genetic
perturbation on the response of cells to exogenous and endogenous exposures at the resolution of individual
cells
. Specifically, we will develop a flexible and scalable in vitro platform for high-throughput single-cell gene-
by-environment interaction screens that couples CRISPR-based single-cell pooled genetic screens to a “nuclear
hashing”-based sample multiplexing strategy and a single-cell genomic readout. This platform will allow for the
simultaneous molecular description of 1,000s-10,000s of unique conditions (i.e. gene and exposure
combinations) at the resolution of individual cell types and cell states. In addition, we propose to develop a set
of tools based on heterologous viral receptor expression for the in situ and cell-type specific delivery of CRISPR-
based genetic perturbations in a manner compatible with single-cell RNA-seq. We highlight the versatility and
generalizability of our approach across three applications of our technologies that aim to define gene-by-
environment interactions in neurobiological disease. We propose to dissect the genetic interactions between
mutations associated with Alzheimer’s disease and the transcriptional response of neural cell types to oxidative
stress and peptide aggregates; to characterize the transcriptional effects associated with cell-type specific
modulation of genetic modifier activity in response to mutations in genes that cause epilepsy disorder and; to
determine how genes that are commonly mutated in brain cancer alter the response of murine tumors to
therapies in vivo. Our goal is to arrive at clinically actionable molecular descriptions of how individual genes
contribute to the response of individuals to exposure.

## Key facts

- **NIH application ID:** 11110037
- **Project number:** 3R35HG011941-04S1
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Jose Luis McFaline-Figueroa
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,773
- **Award type:** 3
- **Project period:** 2021-08-24 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11110037

## Citation

> US National Institutes of Health, RePORTER application 11110037, Defining gene-by-environment interactions using multiplex single-cell genomics (3R35HG011941-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11110037. Licensed CC0.

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