Effects of force and hormonal environment on cervical matrix

描述(由申请人提供)：早产仍然是围产期发病率和死亡率的主要原因，每8个孕妇中就有一个受到先天性出生缺陷的影响。宫颈缩短已被认为是早产的主要危险因素。缩短可能代表着正常机械功能的过早丧失。宫颈已被认为是治疗干预的潜在靶点，但对其调节知之甚少。宫颈细胞外基质的主要功能是维持宫内妊娠。宫颈在怀孕期间经历了生化变化，这降低了它抵抗机械力的能力，机械力被认为是由激素环境和机械应力共同调节的。转化生长因子2(TGF2)信号通路控制着许多组织重塑过程。激素和机械力已被证明可以改变TGF2信号。该项目的目标是确定TGF2在妊娠期间宫颈基质产生中的作用。确定了三个具体目标：1)目的：1.研究TGF2信号对宫颈基质细胞内细胞外基质代谢的影响。确定激素环境(雌激素、孕激素和雄激素)对导致宫颈胶原代谢变化的TGF2信号的影响；目的：确定机械应变对宫颈细胞外基质产生的影响。分子和生物力学技术将被用来评估TGF2信号在细胞外基质产生中的作用。激素环境和机械应力对TGF2信号转导的影响将被研究。通过确定负责宫颈细胞外基质重塑的关键调控因素，可以开发和测试干预措施来预防宫颈衰竭和早产。 公共卫生相关性：早产是导致学习障碍和身体残疾的主要因素。该提案的目标是确定与颈椎功能和细胞外基质重塑相关的治疗干预的新靶点。宫颈细胞外基质负责其维持妊娠至足月的主要机械功能。

DESCRIPTION (provided by applicant): Preterm birth remains the leading cause of perinatal morbidity and mortality after congenital birth defects affecting 1 of every 8 pregnancies. Cervical shortening has been recognized as a major risk factor for preterm birth. Shortening is likely to represent premature loss of normal mechanical function. The cervix has been recognized as a potential target for therapeutic intervention but little is known about its regulation. The principal function of the cervical extracellular matrix is to maintain the pregnancy in utero. The cervix undergoes biochemical changes during pregnancy that reduces its ability to resist mechanical forces that are thought to be mediated by both the hormonal environment and mechanical stress. The transforming growth factor 2 (TGF2) signaling pathway controls many tissue remodeling processes. Hormones and mechanical force have been shown to alter TGF2 signaling. The goal of this project is to determine the role of TGF2 in cervical matrix production during pregnancy. Three specific aims are identified: 1.) To determine the effects of TGF2 signaling on extracellular matrix metabolism within cervical stromal cells; 2.) To determine the effects of hormonal environment (Estrogens, Progestins, and Androgens) on TGF2 signaling leading to changes in cervical collagen metabolism; and 3.) To determine the role of mechanical strain on cervical extracellular matrix production. Molecular and biomechanical techniques will be used to evaluate the role of TGF2 signaling on extracellular matrix production. The effects of both hormonal environment and mechanical stress on TGF2 signaling will be investigated. By identifying key regulatory elements responsible for cervical extracellular matrix remodeling, interventions can be developed and tested to prevent cervical failure and preterm birth. PUBLIC HEALTH RELEVANCE: Preterm birth is a major contributor to learning disabilities and physical handicaps. The goal of this proposal is to identify new targets for therapeutic intervention that relate to cervical function and extracellular matrix remodeling. The cervical extracellular matrix is responsible for its primary mechanical function of maintaining the pregnancy to term.