Individual Predoctoral Dental Scientist Fellowship

个人博士前牙科科学家奖学金

• 批准号: 7489965
• 负责人: Mildred Christine Embree
• 金额: $ 4.17万
• 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/7489965
• 关键词: Animal Model; Apoptosis; Cartilage; Cell Proliferation; Cell physiology; Cells; Chondrocytes; Degenerative polyarthritis; Dental; Diagnostic tests; Differentiation and Growth; Disease; Disease Progression; Early Diagnosis; Event; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fellowship; Functional disorder; Genetic; Goals; Growth Factor; Homeostasis; Immunohistochemistry; Individual; Joints; Lead; Leucine; Maintenance; Modeling; Molecular; Mus; Organ Culture Techniques; Pain; Primary Cell Cultures; Process; Production; Proteins; Proteoglycan; Public Health; Role; Scientist; System; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Testing; Tissues; Transforming Growth Factors; Work; articular cartilage; base; biglycan; early onset; fibromodulin; human TGFB1 protein; improved; in vivo; member; mouse model; pre-doctoral; prevent; tool

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(申请人提供)：颞下颌关节骨关节炎(TMJ OA)是TMJ疾病中最主要的类型之一，但对该疾病的分子机制知之甚少。遗传性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。我们的团队已经建立了一个这样的小鼠模型，在该模型中，缺乏两种细胞外基质(ECM)蛋白的小鼠发生了加速的TMJ骨关节炎。我们建议在软骨组织发生永久性破坏之前研究导致疾病早期发病的细胞机制。BGN和FMOD是富含亮氨酸的小分子蛋白多糖家族的成员，可以调节转化生长因子-β1的活性。转化生长因子-β1是调节和维持软骨内环境平衡的重要生长因子。我们的工作假设是，BGN/fmod缺陷改变了软骨细胞的生长、分化和细胞外基质的产生，这可能是通过对转化生长因子-β1活性的失调而发生的。为了验证我们的假设，我们制定了以下具体目标：1)检测野生型和bgn/fmod缺陷小鼠TMJ软骨的进行性组织病理学变化、细胞外基质组成和细胞变化，包括细胞增殖和细胞凋亡；2)确定转化生长因子-β1在野生型(WT)和bgn/fmod缺陷小鼠(DKO)TMJ软骨调节细胞外基质组成(ECM)和改变细胞过程中的早期机制作用。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提供关于DKO TMJ中哪些因素和细胞事件发生变化的线索。我们对DKO TMJ的特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在DKO中是否发生了变化。我们将使用体外器官培养系统和原代细胞培养来测试外源转化生长因子-β1对我们在体内动物模型中研究的细胞外基质成分和细胞过程的调节作用。 公共卫生关系：颞下颌关节骨关节炎(TMJ OA)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中发现的两种蛋白缺乏的小鼠，Bigylcan和纤维调素，这两种蛋白会加速TMJ OA。我们的目标是利用这个动物模型作为一种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。