Tissue inhibitors of metalloproteinase-1 (TIMP-1) is expressed in the uteri of both menstruating and non-menstruating species. In menstruating species, TIMP-1 is postulated to control the extent of tissue breakdown that occurs during menses. However, as TIMP-1 is expressed beyond the period of menses as well as within the uterus of non-menstruating species, the role of this TIMP within the uterus beyond the regulation of tissue breakdown is uncertain. We have previously demonstrated and present strong supportive evidence in this application, which suggest that TIMP-1 plays a role in uterine development, growth and function. The goal of the proposed application is to expand these preliminary observations and further examine the role of TIMP-1 within the uterus during post-natal uterine development and growth. The hypothesis to be tested is that TIMP-1 controls steroid-regulated uterine development and cell proliferation via a MMP-dependent mechanism which involves modulation of steroid receptor expression within the uterus. We will use TIMP-1 deficient mice and a variety of molecular, cellular and biochemical approaches to test this hypothesis by: 1) examining the spatio-temporal pattern of TIMPs and the function of TIMP-1 during uterine growth and development, 2) determining the mechanisms by which TIMP-1 regulates uterine cell proliferation, and 3) delineating the processes by which TIMP-1 regulates uterine progesterone receptor expression. The proposed experiments will provide new insight into the control of uterine cell proliferation as well as steroid action thereby defining a novel role for TIMP-1 within the uterus. These studies will broaden our understanding on the role of TIMP-1 in uterine physiology and may help to develop new strategies to treat uterine disorders such as infertility, endometriosis and uterine cancer.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD039765-05
Application #
7049209
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yoshinaga, Koji
Project Start
2002-02-01
Project End
2007-01-31
Budget Start
2005-02-03
Budget End
2007-01-31
Support Year
5
Fiscal Year
2005
Total Cost
$236,250
Indirect Cost
Name
University of Kansas
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160