The Role of TIMP-1 in Uterine Physiology

金属蛋白酶组织抑制因子-1(TIMP-1)在月经期和非月经期物种的子宫中均有表达。在月经物种中，TIMP-1被认为控制月经期间发生的组织破坏的程度。然而，由于TIMP-1在月经期之后以及在非月经物种的子宫内表达，这种TIMP在子宫内超出组织分解调节的作用尚不确定。我们之前已经证明并提出了强有力的证据支持这一应用，这表明TIMP-1在子宫发育、生长和功能中发挥作用。拟议应用的目的是扩大这些初步观察，并进一步研究TIMP-1在子宫内在出生后子宫发育和生长中的作用。需要检验的假设是，TIMP-1通过一种依赖于基质金属蛋白酶的机制控制类固醇调节的子宫发育和细胞增殖，该机制涉及调节子宫内类固醇受体的表达。我们将使用TIMP-1缺陷小鼠和各种分子、细胞和生化方法来验证这一假说：1)检测TIMP-1的时空模式以及TIMP-1在子宫生长发育过程中的作用；2)确定TIMP-1调控子宫细胞增殖的机制；3)描述TIMP-1调控子宫孕激素受体表达的过程。拟议的实验将为控制子宫细胞增殖和类固醇作用提供新的见解，从而定义TIMP-1在子宫中的新角色。这些研究将拓宽我们对TIMP-1在子宫生理中的作用的理解，并可能有助于开发治疗不孕不育、子宫内膜异位症和子宫癌等子宫疾病的新策略。

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.