# The role of COPD genetic risk factor HHIP on lymphocytic inflammation

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $169,560

## Abstract

Project Summary
Chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoking, is the third leading cause
of death in the United States. Remarkably, individuals with similar smoking histories have different susceptibility
to develop the disease, and patients display a variable degree of clinical manifestations. Genetic factors may
account for these differences, but the functional, cellular and molecular basis of the variation remains to be
explored. This project aims to bridge knowledge from the genome-wide association studies (GWAS) of COPD
to the pathophysiological mechanisms of the disease by utilizing the observations that (1) inflammatory response
is one of the most prominent differences upon cigarette smoke exposure and (2) a genetic animal model based
on GWAS recapitulates the prominent features of a severe inflammatory response in COPD.
Specifically, we found that genetic mouse models deficient of Hedgehog interacting protein (HHIP), a gene
consistently associated with COPD in GWAS, not only recapitulate robust emphysema susceptibility, but display
a strong inflammatory phenotype similar to human COPD. In particular, an increase in activated CD8+T cells is
observed along the course of emphysema development. Preliminary studies using single cell RNA sequencing
showed that Hhip expression is restricted to lung fibroblasts and absent from immune cells including the
lymphocytes. Moreover, Hhip deficient lung fibroblasts have increased expression of cytokines known to activate
CD8+T cells. These findings led us to hypothesize that reduced HHIP expression in lung fibroblasts leads to an
increase in cytokines and activation of CD8+T cells, and these activated CD8+T cells play a major role in
parenchymal destruction (emphysema). We propose to investigate this hypothesis by the following specific aims:
1. Determine whether CD8+T cell activation depends on Hhip in lung fibroblasts, 2. Determine the functional
importance of lymphocytic activation induced by Hhip-deficiency in smoke-induced lung inflammation and 3.
Determine the relationships between HHIP risk locus and pulmonary lymphocytic inflammation in human
subjects.
Dr. Yun will perform this work under the mentorship of Dr. Hersh, an expert in the field of COPD genomics, Dr.
Zhou, an expert in the field of functional genomics, and Dr. Silverman, an expert in COPD genetic epidemiology.
With the guidance of her mentors and scientific advisory committee composed of distinguished scientists with
expertise related to key areas of this proposal including lung immunology, functional validation and biostatistics,
Dr. Yun has developed a comprehensive five-year training program. This K08 award will support Dr. Yun to
develop the skills needed to become an independent physician-scientist with the long-term goal of understanding
how genetic variation modifies COPD by bridging human ‘omics data and functional validation of candidate
genes.

## Key facts

- **NIH application ID:** 10129421
- **Project number:** 5K08HL146972-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jeong H Yun
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,560
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129421

## Citation

> US National Institutes of Health, RePORTER application 10129421, The role of COPD genetic risk factor HHIP on lymphocytic inflammation (5K08HL146972-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129421. Licensed CC0.

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