# Maintenance of the alveolar niche in emphysema

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $130,613

## Abstract

Project Summary/Abstract
The lung possesses multiple stem/progenitor compartments along the proximal-distal axis where the
epithelial stem/progenitors are situated in close proximity to the underlying stroma. Despite their
homogeneity in appearance, it is increasingly apparent that the lung stroma contains diverse subsets,
each uniquely suited to maintain the nearest stem/progenitor population. Thus, the current gap in
knowledge is not whether stromal compartments are diverse, but rather how segregated stromal
identities are maintained in different niches, and how disruption of distinct stromal identity can lead to
disease. Utilizing a combination of single cell RNA-sequencing and a unique mouse genetic tool we built
to isolate the stroma, our preliminary data demonstrate that hedgehog (Hh) activation promotes proximal
stromal genes while suppressing genes associated with the distal alveolar stroma. Furthermore, distal
expansion of Hh activation in the alveolar stroma attenuates stromal mitogen feedback to the alveolar
stem/progenitors, leading to alveolar loss comparable to emphysema. Relevant to human disease,
genome-wide association studies (GWASes) have identified numerous susceptibility loci for emphysema
near the gene for Hedgehog-interacting protein (HHIP), a negative regulator of Hh activation, but
mechanistic studies to define the pathogenic association have been lacking. Our central hypothesis is
that HHIP, a negative regulator of SHH binding, restricts Hh activation to the proximal stroma to maintain
proximal-distal segregation of stromal identity, the loss of which leads to disruption of the alveolar
stem/progenitor niche and loss of alveoli comparable to emphysema. Leveraging the novel mouse
genetic tools we have developed, our single cell analysis, and our access to clinical specimen, this
proposal aims to address how stromal subsets maintain their distinct identity during normal homeostasis,
how Hh alters the stromal feedback to the alveolar stem/progenitors, and how disruption of the alveolar
niche can lead to chronic lung diseases such as emphysema.

## Key facts

- **NIH application ID:** 10435711
- **Project number:** 3R01HL142552-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Tien Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $130,613
- **Award type:** 3
- **Project period:** 2018-08-22 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435711

## Citation

> US National Institutes of Health, RePORTER application 10435711, Maintenance of the alveolar niche in emphysema (3R01HL142552-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10435711. Licensed CC0.

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