# Understanding and targeting non-genetic mechanisms of drug resistance

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $121,133

## Abstract

PROJECT SUMMARY/ABSTRACT
Drug resistance is one of the key contributing factors to treatment failure in infectious disease. Thus, overcoming
drug resistance would significantly improve patient outcome and reduce healthcare costs. Extensive research
on genetic mechanisms of drug resistance have revealed how drugs are rendered ineffective via changes in the
DNA sequence. However, emerging evidence suggest that non-genetic mechanisms such as chromatin- and
protein-based epigenetic states may explain how drug resistance arises frequently and rapidly. Understanding
the non-genetic mechanisms that drive the evolution of drug resistance could pave the way for the development
of novel therapeutic strategies to combat drug resistance. The Research Training Plan will leverage systems
biology approaches in a leading human fungal pathogen Candida albicans to dissect the molecular underpinning
of pararesistance, a non-genetic mechanism of drug resistance (Aims 1 and 2) and examine the clinical
relevance and therapeutic potential of targeting pararesistance (Aim 3). In Aim 1, the applicant Dr. Jing Lin (Lucy)
Xie will train in single-cell RNA sequencing and ODE modeling in the K99 phase to identify the transcriptional
response and estimate the switching frequency associated with the establishment of pararesistance, developing
a quantitative framework to understand how pararesistance is established. In Aim 2, Dr. Xie will train in pooled
screen with CRISPRi in the K99 phase and complete the analysis in R00 phase to identify regulators of
pararesistance and determine how pararesistance is maintained. In Aim 3, Dr. Xie will establish the prevalence
of pararesistance in a collection of ~1,000 wild C. albicans isolates and identify chemical modulators of
pararesistance in a library of >1,000 bioactive small molecules to investigate the clinical and therapeutic
implications of pararesistance in the R00 phase. The Career Development Plan is designed to provide Dr. Xie
with the opportunity and support to acquire additional expertise in single-cell RNA-sequencing and CRISPRi
technologies and statistical and modeling methodologies, as well as additional professional development training
in teaching, writing, and lab management skills. Mentor Prof. Daniel Jarosz is a leading expert in yeast prions
and non-genetic inheritance. Complementary expertise is offered by co-mentor Prof. James Ferrell (quantitative
biology), and advisors Prof. Ami Bhatt (clinical microbiology) and Prof. Judith Berman (antifungal drug tolerance
and resistance), and collaborators Prof. Michael Hallett (single-cell technologies) and Prof. Rebecca Shapiro
(CRISPR technologies). The Stanford University School of Medicine fosters a highly collaborative and supportive
research environment and provides excellent infrastructures within a vibrant scientific community. In summary,
Dr. Xie will receive high-quality training in research and career development, and is poised to launch her own
independent resea...

## Key facts

- **NIH application ID:** 10867271
- **Project number:** 5K99AI169076-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jing Lin Xie
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $121,133
- **Award type:** 5
- **Project period:** 2023-06-14 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867271

## Citation

> US National Institutes of Health, RePORTER application 10867271, Understanding and targeting non-genetic mechanisms of drug resistance (5K99AI169076-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10867271. Licensed CC0.

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