The Role of TIMP-1 in Uterine Physiology

金属蛋白酶组织抑制剂-1（TIMP-1）在生殖和非生殖物种的子宫中都有表达。 在哺乳动物中，TIMP-1被认为控制月经期间发生的组织分解的程度。然而，由于TIMP-1在月经期之后以及在非生殖物种的子宫内表达，因此该TIMP在子宫内除了调节组织分解之外的作用是不确定的。 我们以前已经证明并提出了强有力的支持性证据，这表明TIMP-1在子宫发育，生长和功能中发挥作用。 该申请的目的是扩大这些初步观察，并进一步研究TIMP-1在产后子宫发育和生长过程中在子宫内的作用。 待检验的假设是TIMP-1通过MMP依赖性机制控制类固醇调节的子宫发育和细胞增殖，所述MMP依赖性机制涉及子宫内类固醇受体表达的调节。 我们将使用TIMP-1缺陷小鼠和各种分子、细胞和生物化学方法来验证这一假设：1）检查TIMP-1在子宫生长和发育过程中的时空模式和TIMP-1的功能，2）确定TIMP-1调节子宫细胞增殖的机制，3）描绘TIMP-1调节子宫孕酮受体表达的过程。 拟议的实验将提供新的洞察子宫细胞增殖的控制以及类固醇的作用，从而定义一个新的作用TIMP-1在子宫内。 这些研究将拓宽我们对TIMP-1在子宫生理学中的作用的理解，并可能有助于开发治疗子宫疾病如不孕症、子宫内膜异位症和子宫癌的新策略。

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.