# COLLAGEN METABOLISM IN A MODEL FOR SCLERODERMA

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 1993 · $196,400

## Abstract

Scleroderma (SSc) is a serious disease of unknown cause characterized by
excessive accumulation of collagen and other connective tissue
components in skin and internal organs.  The mechanisms responsible for
such accumulation are not known.  In previous work from our laboratories
we demonstrated that the Tsk/+ (tight skin) mutant mouse displays
connective tissue abnormalities that closely resemble those present in
patients with SSc, including increased collagen tissue deposition, and
increased biosynthesis in skin organ cultures and cultured fibroblasts.
Furthermore, we demonstrated a coordinated increase in the levels of
type I and type III collagen mRNAs in these cells.  These results
suggest that the Tsk mice are an ideal experimental model for the study
of the connective tissue alterations in SSc.  The purpose of the work
proposed in this application will be to continue our in-depth studies of
the mechanisms responsible for the connective tissue alterations
displayed by Tsk mice at the molecular level applying state of the art
recombinant DNA techniques currently used in our laboratories.  We will
identify the regulatory defect in Tsk mice by mapping pertinent regions
of type I and type VI collagen genes by transient transfections of
intact and deleted putative regulatory sequences of their corresponding
promoters into normal and Tsk/+ fibroblasts and into embryonic cell
lines that are homozygous for the Tsk mutation.  Because of the likely
importance of the Tsk gene in the regulation of collagen gene expression
under normal conditions and in fibrotic diseases such as SSc, we have
initiated studies to identify the location and to clone the Tsk gene
employing intersubspecific backcross studies and chromosome walking.
The function of product(s) of potential candidate genes from the Tsk
region will be identified and the identity of the Tsk gene will be
proved employing transgenic mice.  Biosynthesis and regulation of
collagen in dermal fibroblasts from the newly described Tsk-2 mutant
will be initiated to determine similarities and differences with those
in Tsk/+ fibroblasts and embryonic Tsk/Tsk cell lines and to determine
the molecular basis of the defect.  It is expected that the knowledge
gained from these studies will be of direct relevance to understand the
pathogenesis of the excessive collagen deposition characteristic of SSc
and will provide a more rational approach to develop possible modes of
therapy for this incurable and devastating disease.

## Key facts

- **NIH application ID:** 3156336
- **Project number:** 2R01AR032564-09
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **SAM.gov UEI:** R8JEVL4ULGB7
- **Principal Investigator:** SERGIO A JIMENEZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $196,400
- **Award type:** 2
- **Project period:** 1988-04-01 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156336

## Citation

> US National Institutes of Health, RePORTER application 3156336, COLLAGEN METABOLISM IN A MODEL FOR SCLERODERMA (2R01AR032564-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3156336. Licensed CC0.

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