# Project 2 - Chang

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $457,423

## Abstract

SUMMARY-PROJECT 2-CHANG:
During an immune response to microbial infection, a naive CD8+ T lymphocyte can give rise to terminal effector
cells that provide acute host defense and functionally distinct subsets of memory cells that provide durable
immunity. Generation of one such subset, tissue-resident memory cells (Trm), is now recognized to be
essential for protection at mucosal and body surfaces. Exhaustion, the failure of immune cells to achieve or
maintain optimal function, is an alternative outcome that occurs in the setting of chronic infections and cancer.
Prior studies have advanced our understanding of how CD8+ T cells differentiate into Trm or exhausted cells,
but the field faces several important challenges that this Project seeks to overcome. We propose to take an
unbiased, `phenotypic marker-agnostic' approach exploiting an
innovative sequencing approach that enables
simultaneous measurement of proteins and the transcriptome in the same single cells
to overcome the
inherent limitations of prior studies that have performed transcriptional profiling at the bulk population level. We
will utilize an in vivo shRNA-based approach enabling us to reiteratively evaluate the function of 50 genes
simultaneously, thereby overcoming the slow pace of discovery resulting from traditional genetic knockout
models that evaluate one gene at a time. Specifically, we will use these approaches to achieve the following
goals: (1) Investigate the molecular heterogeneity and functional importance of Trm cells within and among
tissues; (2) Elucidate the ontogeny of Trm cells by reconstructing the transcriptomic roadmap from the naive
state through progressive states of differentiation, within and across tissue sites; (3) Identify early, functionally
important molecular determinants of exhausted circulating and tissue-resident CD8+ T cells. A major strength
of our proposal is the integrated and synergistic design that exploits the strength of the individual Project and
Core Principal Investigators, generating datasets that inform multiple Projects. We envision that insights
resulting from our studies may have important implications for the rational design of vaccines and for
therapeutic interventions that reverse the exhausted state.

## Key facts

- **NIH application ID:** 9960426
- **Project number:** 5P01AI132122-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** John T Chang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,423
- **Award type:** 5
- **Project period:** 2018-07-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960426

## Citation

> US National Institutes of Health, RePORTER application 9960426, Project 2 - Chang (5P01AI132122-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9960426. Licensed CC0.

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