CAREER: Understanding the Micromechanisms of Growth and Remodeling of Collagenous Tissues

该学院早期职业发展（CAREER）奖的研究目标是研究胶原组织生长和重塑的基本微观机制。胶原蛋白结构赋予包括血管、皮肤和角膜在内的各种软组织硬度、强度和韧性。机械刺激可以通过各种主动细胞机制和被动微观机制改变胶原结构的产生和组织，导致生长和重塑。 该研究将集中在一个模型生物组织，实验性青光眼小鼠眼睛的巩膜受到慢性眼内压（IOP）升高。 我们假设巩膜响应病理负荷的生长和重塑受到3种微观机制的强烈影响：（1）应变诱导的胶原降解和积累，（2）胶原卷曲重塑，和（3）肌成纤维细胞（细胞）基质收缩。 拟议的工作将开发新的实验方法，包括使用共聚焦显微镜和数字体积相关（DVC）的膨胀实验，以测量慢性IOP升高引起的机械性能，胶原结构和细胞特征的变化;以及基于3种假设机制的生长和重塑的组成模型。如果成功，这些研究将大大有助于理解机械负荷如何影响胶原组织的生长和重塑。 这将直接转化为一系列疾病的研究和治疗，如肌腱损伤，心脏纤维化和青光眼。该提案的基础研究对公共卫生很重要，因为青光眼是世界上第二大致盲原因。 该教育计划的重点是生物力学课程的开发，并为高中生，本科生和研究生创造参与生物力学研究的机会。 该研究计划是多学科和合作的性质。所有学生研究人员将与眼科医生和生物药理学家合作者密切互动，学习传统工程教育中没有的广泛知识。

The research objective of this Faculty Early Career Development (CAREER) award is to investigate the fundamental microscale mechanisms of growth and remodeling of collagenous tissues. Collagen structures impart stiffness, strength, and toughness to a variety of soft tissues including blood vessels, skin, and the cornea. Mechanical stimuli can alter the production and organization of collagen structures, leading to growth and remodeling, through a variety of active cellular mechanisms and passive microscale mechanisms. The research will focus on a model biological tissue, the sclera of experimental glaucoma mouse eyes subjected to chronic intraocular pressure (IOP) elevation. We hypothesize that growth and remodeling of the sclera in response to pathological loading is strongly influenced by 3 microscale mechanisms: (1) strain-induced collagen degradation and accumulation, (2) collagen crimp remodeling, and (3) myofibroblast (cellular) matrix contraction. The proposed work will develop new experimental methods, including an inflation experiment using confocal microscopy and a digital volume correlation (DVC), to measure changes in mechanical properties, collagen structure, and cellular features caused by chronic IOP elevation; and constitutive models for growth and remodeling based on the 3 hypothesized mechanisms. If successful, these studies will add significantly to understanding how mechanical loading influences growth and remodeling of collagen tissues. This will have direct translation to the study and treatment of a range of diseases, such as tendon injuries, cardiac fibrosis, and glaucoma. The basic research of the proposal is important to public health, because glaucoma is the second leading cause of blindness in the world. The educational program focuses on course development on biomechanics and on creating opportunities for high school, undergraduate, and graduate students to participate in biomechanics research. The research program is multidisciplinary and collaborative in nature. All student investigators will interact closely with ophthalmologist and biophysicist collaborators to learn a breadth of knowledge not found in traditional engineering education.