# Engineered alveolar organoids to understand ECM signaling

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2020 · $123,850

## Abstract

PROJECT ABSTRACT
Idiopathic pulmonary fibrosis (IPF) of the distal lung is characterized by spatially heterogeneous areas of
fibroblasts/myofibroblasts and accumulation of excess extracellular matrix (ECM) that disrupts the alveolar
architecture. Alveolar epithelial cells are now thought to directly contribute to the development and progression
of fibrosis, but how new ECM deposition impacts alveolar epithelia function and feedbacks to reinforce fibrotic
remodeling is unknown. This is due in part to the lack of tools to study ECM dynamics or to directly measure cell
fate in response to altered ECM in vivo. Organoid cultures can generate an in vivo-like complement of alveolar
tissue; however, current in vitro models depend on the use of Matrigel matrices, which feature variable
compositions and is not conducive to controlled manipulations.
 The overall focus of the proposed work is to connect changes in secreted alveolar ECM cues and
epithelial cell function (K99 phase) and epithelia to mesenchyme signaling (R00). During the K99 phase, defined
hydrogel matrices will be developed to form alveolar organoids in a defined microenvironment and determine
how newly secreted ECM composition and mechanics guide epithelial cell function. Using this platform, the
secreted ECM will be externally crosslinked to examine whether ECM stiffening promotes epithelial cells
dysfunction. With an understanding of how secreted ECM initiates epithelial cell dysfunction, the second aim will
determine how the secreted ECM alters the response of epithelial cells to signals from the mesenchyme during
the R00 phase. We will determine if the accumulation of ECM changes the interaction between AT2 cells and
mesenchymal cells, and whether this reinforces fibrotic remodeling. Next, microstructured hydrogels will be used
to control for spatial relationships and examine the effect of the physical separation of epithelial and
mesenchymal cells on epithelial cell function.
 To understand the bidirectional signaling of cells and their continuously changing surroundings within the
alveolar niche, this research will use organoid cultures and engineering approaches to manipulate and
deconstruct cell-ECM interactions. The outcomes will comprise identification of new ECM mediated mechanisms
involved in alveolarization and reparative processes, and provide new avenues for testing therapeutics
modulating paracrine signaling pathways involved in IPF. Importantly, this proposal comprises a rigorous training
plan that will build the foundation to advance the applicant’s career in biomedical research. Specifically, the K99
training will consist of learning mouse models, lineage tracing, and primary cell isolation to establish the
foundation towards investigating cell-cell signaling using engineered hydrogels during the independent
investigator R00 phase.

## Key facts

- **NIH application ID:** 9949086
- **Project number:** 1K99HL151670-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Claudia Loebel
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,850
- **Award type:** 1
- **Project period:** 2020-08-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949086

## Citation

> US National Institutes of Health, RePORTER application 9949086, Engineered alveolar organoids to understand ECM signaling (1K99HL151670-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9949086. Licensed CC0.

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