# THE BIOLOGICAL ROLE OF HUMAN TIMP IN MATRIX TURNOVER

> **NIH NIH R01** · JEWISH HOSPITAL OF SAINT LOUIS · 1993 · $224,778

## Abstract

The turnover of extracellular matrix is crucial for maintaining
structural integrity of connective tissues, and aberrations in this
process can lead to  a variety of pathologic states.  The activity of a
group of neutral metalloproteinases, including interstitial collagenase,
stromelysin, 72 kD type IV collagenase, and 92 kD gelatinase/type V
collagenase is believed to control the turnover of extracellular matrix
components.  Tissue inhibitor of metalloproteinases, or TIMP, functions
as the major, and probably, only, inhibitor of this entire family of
neutral metalloproteinases within the interstitial spaces of connective
tissues.  The broad objective of this grant proposal is to study the
biochemical mechanisms of action, molecular regulation, and in situ
production of TIMP during normal matrix turnover and in disease states.

Studies of the biochemical mechanisms of TIMP action will encompass
several areas, including its capacity to complex zymogen versus active
forms of the various metalloproteases, as assessed HPLC gel-filtration
techniques.  Furthermore, affinities between TIMP and the different
enzymes will be determined using cross-linking reagents or by kinetic
analyses against highly susceptible substrates.  Localization of the
structural sites in TIMP and metalloproteinases that are required for
enzyme-inhibitor binding is a major priority and will be approached
using covalent cross-linking reagents that can be iodinated, with
transfer of the label to a second protein, and subsequent
isolation/sequencing of the iodinated fragment(s).

Studies of regulatory mechanisms will investigate the role of cell-
matrix interactions in TIMP and collagenase biosynthesis and the
consequences to matrix degradation.  Cytokines and biologic factors such
as gamma-interferon and LPS will be studied for capacity to regulate
TIMP and collagenase expression at protein and mRNA levels.  Retinoids
will  be further investigated with regards to potential transcriptional
mechanisms of their effects.

In situ hybridization will be performed on isolated cells and whole
tissues specimens to gain insights in the cell types actively
synthesizing TIMP and collagenase during normal connective tissue
turnover and in disease processes.  The cellular expression of these
proteins during fetal development, actinic injury and in connective
tissue diseases, and epidermolysis bullosa will be studied.

## Key facts

- **NIH application ID:** 3157370
- **Project number:** 5R01AR035805-10
- **Recipient organization:** JEWISH HOSPITAL OF SAINT LOUIS
- **Principal Investigator:** HOWARD G WELGUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $224,778
- **Award type:** 5
- **Project period:** 1984-12-01 → 1994-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3157370

## Citation

> US National Institutes of Health, RePORTER application 3157370, THE BIOLOGICAL ROLE OF HUMAN TIMP IN MATRIX TURNOVER (5R01AR035805-10). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3157370. Licensed CC0.

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