# Mechanisms of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $440,000

## Abstract

Hermansky-Pudlak Syndrome (HPS) is a family of autosomal recessive disorders characterized by
oculocutaneous albinism and highly penetrant pulmonary fibrosis. Despite knowledge of the underlying genetic
defects, there are currently no therapeutic or preventative approaches for HPS pulmonary fibrosis. Our
published data demonstrate that alveolar epithelial cells (AECs) are the primary drivers of fibrotic susceptibility
in HPS; however, the underlying mechanisms by which AECs dysfunction results in fibrosis remain undefined
and represent an important knowledge gap in the field of fibrosis research. Studies during the current funding
period have enabled us to define key phenotypes of HPS AECs with connections to fibrotic susceptibility in
HPS mice. Specifically, we showed excess production of MCP-1 and increased Nox4-mediated ROS
production by AECs contributes to fibrosis. A major goal of this proposal is to define how these pro-fibrotic
AEC phenotypes relate to the underlying molecular defect in HPS. In search of a mechanism that underlies
the observed pro-fibrotic phenotype of AECs in HPS, we recently identified increased TGFβ pathway activation
in unstimulated HPS AECs. Activated type I and type II TGFβ receptors are constitutively recycled into
endosomes, and early endosomes have been recognized as a vital signaling organelle for TGFβ signaling.
Based on our preliminary data, we propose to investigate how compromised endosomal trafficking resulting
from the genetic defect in HPS2 (loss of AP-3) alters proteostasis and dysregulates TGFβ signaling and AEC
function. Our hypothesis is that defective endosomal trafficking in HPS alters TGFβ receptor signaling, thereby
resulting in persistent and increased Smad and Erk1/2 signaling. These altered signaling pathways result in
increased expression of MCP-1, Nox4, and other mediators by AECs that create a pro-fibrotic
microenvironment in the distal lung. To test this hypothesis, we propose the following specific aims using cell
culture models and a disease relevant HPS mouse model that develops spontaneous and progressive fibrosis
with aging: 1) to determine how loss of AP-3 results in increased TGFβ signaling and expression of pro-fibrotic
mediators by AECs, 2) to determine how AECs promote fibroblast activation in HPS, and 3) to investigate
mechanisms of pulmonary fibrosis in HPS that develops with aging. Defining the mechanisms of AEC
dysfunction in HPS could provide new insights into pathogenesis of HPS and other forms of pulmonary fibrosis,
thus facilitating development of new therapeutic and preventative strategies for this fatal disorder.

## Key facts

- **NIH application ID:** 10165784
- **Project number:** 5R01HL119503-10
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Lisa R. Young
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,000
- **Award type:** 5
- **Project period:** 2013-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165784

## Citation

> US National Institutes of Health, RePORTER application 10165784, Mechanisms of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome (5R01HL119503-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165784. Licensed CC0.

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