Individual Predoctoral Dental Scientist Fellowship

个人博士前牙科科学家奖学金

• 批准号: 7222548
• 负责人: Mildred Christine Embree
• 金额: $ 4.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-16 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222548
• 关键词: apoptosis; cartilage; chondrocytes; chondroitin sulfates; diagnostic tests; extracellular matrix; genetics; growth factor; joints; lead; model; osteoarthritis; proteins; proteoglycan; role; tissues; transforming growth factors

DESCRIPTION (provided by applicant): Temporomandibular joint osteoarthritis (TMJ OA) is one of the most predominant types of TMJ disorders, yet little is known about the molecular mechanisms underlying the disease. Genetic animal models can be used as scientific tools to investigate the mechanistic basis for temporomandibular joint osteoarthritis (TMJ OA). Our group has generated one such mouse model where mice deficient in two extracellular matrix (ECM) proteins, biglycan (BGN) and fibromodulin (FMOD) develop accelerated TMJ OA. We propose to study the cellular mechanisms contributing to the early onset of the disease before permanent destruction of the cartilage tissue occurs. BGN and FMOD are members of the small leucine-rich proteoglycan family and can modulate transforming growth factor-beta1 activity (TGF-beta1). TGF-beta1 is a critical growth factor for regulating and sustaining cartilage homeostasis. Our working hypothesis is that bgn/fmod deficiency alters chondrocyte growth, differentiation, and ECM production that might occur through the dysregulation of TGF-beta1 activity. To test our hypothesis, the following specific aims have been formulated: 1) examine the progressive histopathological changes, extracellular matrix composition and cellular changes including cell proliferation and cell apoptosis in the TMJ cartilage of wildtype and bgn/fmod deficient mice; and 2) determine the early mechanistic role of TGF-beta1 in regulating extracellular matrix composition (ECM) and altered cell processes in the TMJ cartilage of wildtype (WT) and bgn/fmod deficient mice (DKO). A comprehensive in vivo analysis of our TMJ OA model as the disease progresses will provide clues as to what factors and cellular events are changed in the DKO TMJ. Our characterization of the DKO TMJ will include the examination of the expression of ECM proteins that are critical for cartilage maintenance by immunohistochemistry. We will also examine cellular proliferation and cellular apoptosis in order to detect if these cellular processes are altered in the DKO. We will use an ex vivo organ culture system and primary cell cultures to test the effects of exogenous TGF-beta1 on regulating the ECM composition and cellular processes we investigate in our in vivo animal model. PUBLIC HEALTH RELAVANCE: Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease that leads to permanent tissue destruction, joint dysfunction, and disabling pain. We have generated mice deficient in two proteins found in the TMJ, bigylcan and fibromodulin, that develop accelerated TMJ OA. Our goal is to use this animal model as a scientific tool to investigate the early cellular events contributing to the onset of TMJ OA to help improve effective diagnostic tests and therapies.

描述（由申请人提供）：颞下颌关节骨关节炎（TMJ OA）是最主要的TMJ疾病类型之一，但对该疾病的分子机制知之甚少。遗传动物模型可作为研究颞下颌关节骨关节炎（TMJ OA）发病机制的科学工具。我们的小组已经产生了一个这样的小鼠模型，其中缺乏两种细胞外基质（ECM）蛋白，双糖蛋白聚糖（BGN）和纤维调节蛋白（FMOD）的小鼠发展加速TMJ OA。我们建议在软骨组织发生永久性破坏之前研究有助于疾病早期发作的细胞机制。BGN和FMOD是富含亮氨酸的小蛋白聚糖家族的成员，可以调节转化生长因子-β 1活性（TGF-β 1）。TGF-β 1是调节和维持软骨稳态的关键生长因子。我们的工作假设是，bgn/fmod缺陷改变软骨细胞的生长，分化和ECM的生产，可能会发生通过TGF-β 1活性失调。为了验证我们的假设，我们制定了以下具体目标：1）检查野生型和bgn/fmod缺陷小鼠TMJ软骨中进行性组织病理学变化，细胞外基质成分和细胞变化，包括细胞增殖和细胞凋亡;和2）确定TGF-β 1在调节细胞外基质成分（ECM）中的早期机制作用以及野生型（WT）和bgn/fmod缺陷小鼠（DKO）的TMJ软骨中改变的细胞过程。随着疾病的进展，对我们的TMJ OA模型进行全面的体内分析，将为DKO TMJ中哪些因素和细胞事件发生变化提供线索。我们对DKO TMJ的表征将包括通过免疫组织化学检查对软骨维持至关重要的ECM蛋白的表达。我们还将检查细胞增殖和细胞凋亡，以检测这些细胞过程是否在DKO中改变。我们将使用离体器官培养系统和原代细胞培养来测试外源性TGF-β 1对调节ECM组成和细胞过程的影响，我们在体内动物模型中进行了研究。 公共卫生关系：颞下颌关节骨关节炎（TMJOA）是一种退行性关节疾病，可导致永久性组织破坏、关节功能障碍和致残性疼痛。我们已经产生了在TMJ中发现的两种蛋白质，双糖蛋白聚糖和纤维调节蛋白缺陷的小鼠，其发展加速的TMJ OA。我们的目标是使用这种动物模型作为科学工具来研究导致TMJ OA发病的早期细胞事件，以帮助改进有效的诊断测试和治疗。