MODULATION OF TMJ DEGRADATION BY RELAXIN AND ESTROGEN

松弛素和雌激素对颞下颌关节退化的调节

• 批准号: 6634578
• 负责人: SUNIL D KAPILA
• 金额: $ 9.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634578
• 关键词: collagenase; disease /disorder etiology; enzyme induction /repression; enzyme inhibitors; estradiol; estrogen receptors; estrogens; female; gene induction /repression; genetic promoter element; hormone regulation /control mechanism; laboratory rabbit; oral pharyngeal disorder; receptor expression; relaxin; temporomandibular joint; temporomandibular joint syndrome; transcription factor

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.

该提案描绘了一个结构化的 5 年职业发展计划，将帮助申请人有效且高效地实现其研究职业目标。它定义了一个全面且有凝聚力的计划，其中包括新颖的研究领域、参与正式的基础生物医学科学课程以及转化研究方法学课程的开发。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。尽管颞下颌疾病具有使人衰弱的性质并且对育龄妇女有偏爱，但颞下颌疾病的病因和发病机制仍然未知。申请人最近的发现是，松弛素增加TMJ盘纤维软骨细胞中基质金属蛋白酶(MMP)胶原酶-1和溶基质素-1的表达，但在滑膜细胞中不增加，这表明该激素在TMJ疾病中的潜在作用机制。此外，松弛素对这些 MMP 的诱导作用通过细胞事先暴露于 β-雌二醇而增强。这些观察结果表明，椎间盘细胞可能是松弛素基质降解作用的特定靶位点。因此，研究提出的最重要的假设是松弛素和雌激素通过增加关节细胞中 MMP 的表达并减少其抑制剂和胶原蛋白的表达而导致女性 TMJ 疾病。根据最近的研究结果，R29 资助的具体目标已扩大到包括以下研究：(I) 鉴定参与松弛素诱导胶原酶-1 的启动子位点和转录因子，以及 (2) 阐明 β-雌二醇增强这种诱导的机制。这些研究将深入了解松弛素和 β-雌二醇对胶原酶-1 的分子调节。总之，R29 的发现和拟议的研究对于设计女性颞下颌关节疾病的具体诊断方法和合理治疗可能至关重要。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）增强其正在进行的研究的规模和深度，以及（3）为ROl拨款申请生成额外的数据。从长远来看，这段密集的研究相关活动将成为他成为一名有能力且成功的转化研究员的目标的跳板。独立科学家奖对于实现这些目标至关重要。