# Investigating the role of cell-mediated collagen turnover in regulating tissue fibrosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $467,447

## Abstract

PROJECT SUMMARY
Pulmonary fibrosis occurs when collagen production outpaces collagen degradation. The long-term goal is to
understand the role of cell-mediated collagen degradation in regulating the severity of pulmonary fibrosis. The
overall objective of this application is to elucidate the mechanisms by which 2 genes identified through a high-
throughput screen of collagen turnover, Fatty Acid Synthase (FAS) and Cell Division Cyclase-like Related Protein
Kinase (CDC7), regulate cell-mediated collagen turnover coupled with investigating the role in collagen turnover
in human cells of candidate genes identified through the screen that when silenced increase collagen uptake.
The central hypothesis is that cell-mediated clearance of collagen fragments regulates the severity of pulmonary
fibrosis. Specifically, FAS-mediated production of lipid mediators promotes while CDC7 regulation of collagen
endocytic machinery inhibits cellular uptake of collagen. An additional hypothesis is that there are genetic
controls that prevent cells from engaging in matrix degradation and that silencing of these genes can augment
collagen resorption thereby promoting resolution of tissue fibrosis. These hypotheses are built on data
demonstrating that (1) RNAi-mediated silencing of FAS and CDC7 in Drosophila and mammalian cells leads to
reduced and increased collagen uptake respectively; (2) pharmaceutical inhibition of CDC7 leads to increased
collagen uptake and increased expression of collagen endocytic machinery; and (3) published work
demonstrating that treatment with fatty acids reverses established lung fibrosis in mice by increasing collagen
turnover; and (4) RNAi mediated silencing of a number of genes in Drosophila increases cell-mediated collagen
turnover. These hypotheses will be tested through 3 specific aims: 1) Determining the role of FAS-mediated
palmitoylation in regulating collagen endocytosis; determining the role of Flotillin-2 in resolving lung fibrosis by
promoting collagen uptake; 2) Investigating whether CDC7 regulates collagen turnover by inhibiting expression
of collagen degradation pathways; 3) Investigating whether silencing of mammalian orthologs of candidate genes
identified in the Drosophila screen leads to an increase in cell-mediated collagen uptake. Aim 1 will examine the
role of FAS-mediated palmitoylation of the vesicular transport proteins, Flotillin 1 and 2, in regulating the collagen
endocytic machinery required for collagen uptake as well as the effect of in vivo transgenic deletion of Flotillin 2
on the severity of bleomycin-induced pulmonary fibrosis. Aim 2 will examine the role of CDC7 in regulating
expression of Endo180 and other mediators of collagen turnover and the effect of in vivo inhibition of CDC7 on
macrophage-mediated collagen uptake. Aim 3 will examine the role in collagen turnover in mammalian cells of
candidate genes identified through a Drosophila screen that when silenced increase collagen uptake. The
proposed res...

## Key facts

- **NIH application ID:** 9836869
- **Project number:** 5R01HL136377-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KAMRAN ATABAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,447
- **Award type:** 5
- **Project period:** 2017-12-25 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836869

## Citation

> US National Institutes of Health, RePORTER application 9836869, Investigating the role of cell-mediated collagen turnover in regulating tissue fibrosis (5R01HL136377-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836869. Licensed CC0.

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