# Illuminating cellular dark matter through the development of novel chemical tools

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $89,803

## Abstract

PROJECT SUMMARY
There is a vast repertoire of species within cells for which we have a poor understanding of their function and
biomolecular interactions. These species can be referred to as the “dark matter” of biology, as their mechanism
of action is hidden from conventional observation. Our laboratory seeks to illuminate the function of cellular “dark
matter” through the development of new chemical technology. The proposed research program will pursue two
major research thrusts. First, we plan to develop tools for site-specific RNA modification, and apply these tools
for the manipulation, imaging, and isolation of disease relevant RNA protein complexes. We will create tools for
use in live cells and develop the ability to covalently recruit proteins to RNA, forming RNA-protein
macromolecular conjugates. The technology will be applied to study RNAs implicated in disease. Specifically,
we are interested in characterizing the pathways of pathogenicity for the C9orf72 nucleotide repeat expansion
RNA, which is thought to play a major role in genetic amyotrophic lateral sclerosis (ALS). In the second thrust,
we will carry out the in situ synthesis of lipid species within living cells, with the goal of uncovering the molecular
mechanism by which enigmatic lipid species affect cell behavior. We plan to develop approaches enabling the
selective and bioorthogonal delivery of sphingolipids to living cells. Building upon technology previously
developed in our lab, we will deliver cell permeable lipid precursors which will spontaneously assemble into
functional lipids within the cell. Leveraging this approach, we will create photoaffinity probes for the pulldown of
sphingolipid-interacting proteins, with the goal of elucidating the protein partners of the non-canonical
deoxysphingolipid 1-deoxydihydroceramide, which is cytotoxic and implicated in several diseases. Realization
of our research program goals would improve our knowledge of cell biology and lead to the development of new
tools for interrogating RNA and lipid species. Our long-term vision is to create and apply technology that enables
improved mechanistic understanding of biomolecular interactions, leading to an increased understanding of
human disease, and accelerating the development of possible therapeutic interventions.

## Key facts

- **NIH application ID:** 10581981
- **Project number:** 3R35GM141939-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Neal Krishna Devaraj
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $89,803
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581981

## Citation

> US National Institutes of Health, RePORTER application 10581981, Illuminating cellular dark matter through the development of novel chemical tools (3R35GM141939-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10581981. Licensed CC0.

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