MODULATION OF TMJ DEGRADATION BY RELAXIN AND ESTROGEN

这份提案勾勒出了一个结构化的5年职业发展计划，将帮助申请者有效和高效地实现其研究职业目标。它定义了一个全面而有凝聚力的计划，包括新的研究领域，参与正式的基础生物医学课程，以及在翻译研究方法方面的课程开发。该计划的研究部分旨在确定女性生殖激素松弛素和雌激素在女性颞下颌关节(TMJ)疾病发病机制中的作用。尽管其衰弱的性质和倾向于育龄妇女，但其病因和发病机制仍不清楚。申请人最近发现，松弛素能增加TMJ间盘纤维软骨细胞中基质金属蛋白酶(MMPs)胶原酶-1和基质分解酶-L的表达，但不能增加滑膜细胞的表达，这表明这种激素在TMJ疾病中的潜在作用机制。此外，松弛素对这些MMPs的诱导作用会因细胞预先暴露于β-雌二醇而增强。这些观察结果表明，视盘细胞可能是松弛素基质降解作用的特定靶点。因此，研究提出的压倒一切的假设是，松弛素和雌激素通过增加关节细胞中MMPs的表达，减少其抑制物和胶原的表达，从而导致女性TMJ疾病。根据最近的发现，R29赠款的具体目标已扩大到包括以下研究：(I)确定松弛蛋白诱导胶原酶-1的启动子位置和转录因子，以及(2)阐明β-雌二醇增强这种诱导的机制。这些研究将为松弛素和β-雌二醇对胶原酶-L的分子调控提供新的思路。总而言之，R29和拟议研究的结果可能对设计女性TMJ疾病的特定诊断方法和合理治疗至关重要。这项研究将得到细胞、发育、结缔组织和生殖生物学以及生物信息学方面的相关前沿课程的补充。该计划的短期目标是(I)加强申请人对当代分子和细胞生物学技术的理解，(2)加强其正在进行的研究的规模和深度，以及(3)为ROL拨款申请产生额外的数据。从长远来看，这段与研究相关的密集活动将成为他成为一名称职和成功的翻译研究人员目标的跳板。独立科学家奖将是实现这些目标的关键。

This proposal delineates a structured 5-year career development plan that will help the applicant to effectively and efficiently achieve his research career goals. It defines a comprehensive and cohesive program incorporating novel areas of research, participation in formal basic biomedical science courses, and the development of a course in translational research methodologies. The research component Of this program aims to identify the role of the female reproductive hormones relaxin and estrogen in the etiopathogenesis of temporomandibular joint (TMJ) disease in women. Despite their debilitating nature and predilection for women of reproductive age, the etiology and pathogenesis of temporomandibular disorders remain unknown. The applicant's recent findings that relaxin increases the expression of the matrix metalloproteinases (MMPs) collagenase-1 and stromelysin-l in TMJ disc fibrocartilaginous cells, but not in synoviocytes, suggests a potential mechanism of action for this hormone in TMJ diseases. Furthermore, relaxin's induction of these MMPs is potentiated by prior exposure of the cells to beta-estradiol. These observations suggest that disc cells may be specific target sites for the matrixdegradative effects of relaxin. Therefore, the overriding hypothesis proposed studies is that relaxin and estrogen cause TMJ disease in women by increasing the expression of MMPs and decreasing that of their inhibitors and collagen in joint cells. On the basis of recent findings, the specific aims of the R29 grant have been expanded to include studies to (I) identify the promoter sites and transcription factors involved in the induction of collagenase-1 by relaxin, and (2) elucidate the mechanisms by which beta-estradiol potentiates this induction. These studies will provide insights into the molecular regulation of collagenase-l by relaxin and beta-estradiol. Together, the findings of the R29 and proposed studies may be critical in designing specific diagnostic methods and rational treatments for TMJ diseases in women. This research will be complemented by relevant cutting-edge courses in cell, developmental, connective tissue and reproductive biology and in bioinformatics. The short-term goals of this program are to (I) strengthen the applicant's understanding of contemporary molecular and cell biology techniques, (2) enhance the magnitude and depth of his ongoing studies, and (3) generate additional data for an ROl grant application. In the long-term, this period of intensive research-related activity will serve as a springboard for his goal of becoming a competent and successful translational researcher. The Independent Scientist Award will be critical in achieving these goals.