Nanomechanics of Cartilage Extracellular Matrix Macromolecules from Aged, Diseased, and Engineered Tissues

该奖项的研究目标是研究老化、病变和工程软骨组织的细胞外基质大分子的超微结构和生物物理特性。将采用一套新的基于原子力显微镜的成像和纳米力学方法，结合传统的生化技术，实现四个具体目标。首先（Aim 1），将量化和比较年龄和骨关节炎（OA）降解对人软骨聚集蛋白纳米分子结构的影响。其次（目标2），在目标1中研究的人类聚合体的纳米力学特性（例如平衡/动态压缩和剪切特性，生物分子自粘附等）将被测量、比较，并与分子结构（目标1）相关，作为母软骨组织的年龄和OA降解程度的函数。第三（Aim 3），分析组织工程支架中软骨细胞和骨髓源性祖细胞体外成软骨合成的聚集蛋白。最后（Aim 4），将研究施加于组织工程软骨结构的宏观静态和动态压缩载荷对聚集蛋白分子结构-纳米力学性能的影响。本研究计划将阐明软骨功能的关键分子机制起源，以及退变和OA疾病的病理。此外，新的纳米技术方法将应用于软骨组织工程，这在改善先天性疾病、创伤性损伤和退行性过程（如衰老）的治疗方面具有巨大的潜力。该计划的多样性组成部分包括；招募所有学术水平的少数族裔学生参与研究项目，在以少数族裔为基础的科学和工程会议上举办年度技术专题讨论会，为全国各地的少数族裔博士后研究生参加为期2.5天的“未来教师研讨会”，并通过成为PBS儿童电视节目和多媒体项目顾问委员会成员的身份进行推广。

The research objective of this award is to investigate the ultrastructure and biophysical properties of extracellular matrix macromolecules from aged, diseased, and engineered cartilage tissue. A suite of novel atomic force microscopy-based imaging and nanomechanical methodologies will be employed, in conjunction with traditional biochemical techniques, to carry out four specific aims. Firstly (Aim 1), the effects of age and osteoarthritic (OA) degradation on the nanomolecular architecture of human cartilage aggrecan will be quantified and compared. Secondly (Aim 2), the nanomechanical properties (e.g. equilibrium/dynamic compressive and shear properties, biomolecular self-adhesion, etc.) of the human aggrecan studied in Aim 1, will be measured, compared, and related to molecular architecture (Aim 1) as a function of the age and extent of OA degradation of the parent cartilage tissue. Thirdly (Aim 3), aggrecan synthesized by chondrocytes and marrow-derived progenitor cells undergoing chondrogenesis in vitro in tissue engineered scaffolds will be analyzed. Lastly (Aim 4), the effect of macroscopic static and dynamic compressive loading applied to tissue engineered cartilage constructs on the molecular structure-nanomechanical properties of aggrecan will be studied.This research program will elucidate the critical molecular mechanistic origins of cartilage functionality as well as the pathology of degeneration and OA disease. In addition, novel nanotechnological methodologies will be applied to cartilage tissue engineering which holds great potential for advancement towards improved treatments of congenital diseases, traumatic injuries, and degenerative processes such as aging. The diversity component of this program includes; the recruitment of underrepresented minority (URM) students at all academic levels to the research program, the development of an annual technical symposia at a URM-based science and engineering conference, participation in a 2.5 day "Future Faculty Workshop" for URM graduate students in postdocs from around the country, and outreach via membership on the advisory board for a PBS children's television show and multimedia project.