Regulation of Focal Adhesion Initiation by Lipids and Membrane Bending

该奖项的研究目标是了解细胞如何粘附在诸如天然细胞外基质和生物材料中使用的人造表面等表面的早期部分。具体而言，本研究将探讨膜如何控制脂质运输和重要粘附分子向粘附斑块的募集。这些实验将使用先进的显微镜，能够测量这些结构中的细胞粘附动力学和分子动力学。如果成功，这些测量将有助于更好地理解细胞粘附动力学，以及为什么动脉粥样硬化病变形成于低和振荡流体剪切应力区域，如血管分叉处和支架附近。它也可能对剪切诱导的血管舒张很重要，这是已知的对抗压力诱导的小动脉肌原性收缩，因此是血压控制和高血压的重要组成部分。如果成功，这些研究将显著增加该领域对机械传感的理解，特别是对质膜分子尺度功能组织的理解。这种理解可能有助于未来力学感觉理论的测试和新的生物力学模拟物的发展，如含有蛋白质、蛋白聚糖和细胞骨架的单层囊泡。由于几乎所有细胞都需要感知和施加力，这些研究可能对许多机械生物学过程具有广泛的意义，包括骨重塑、干细胞分化和发育生物学。建议的膜力学生物学研究将纳入研究生训练和本科生荣誉论文准备。这次培训将成为向年轻科学家（6-12年级）拓展的基础，其中分子尺度的机械生物学通过现代3-D可视化变得更容易理解。这样的拓展将为那些代表性不足的群体提供机会，比如妇女、少数民族和宾夕法尼亚州农村地区的学生，他们在考虑高等教育选择时经常访问宾夕法尼亚州立大学。

The research objective of this award is to understand the very early parts of how cells adhere to surfaces such as natural extracellular matrices and artificial surfaces used in biomaterials. Specifically, this research will investigate how the membrane controls the transport of lipids and the recruitment of important adhesion molecules to adhesion plaques. These experiments will use advanced microscopes capable of measuring dynamics of cellular adhesions and molecular dynamics in these structures. If successful, these measurements would lead to a better understanding of cellular adhesion dynamics and why atherosclerotic lesions form in areas of low and oscillating fluid shear stress such as at blood vessel bifurcations and near stents. It may also be important for shear-induced vasodilation, which is known to counteract pressure-induced myogenic constriction in small arteries and thus is an important component of blood pressure control and hypertension. If successful, these studies would add significantly to the field's understanding of mechanosensing in particular and molecular scale functional organization of plasma membranes in general. This understanding may assist in future testing of mechanosensation theories and in the development of new biomechanical mimetics, such as unilamellar vesicles with proteins, proteoglycans, and cytoskeleton. Since almost all cells need to sense and apply force, these studies may have broad implications for many mechanobiological processes including bone remodeling, stem cell differentiation, and developmental biology. The proposed research on membrane mechanobiology will be integrated into graduate training and in undergraduate honors thesis preparation. This training will form the basis of outreach to young scientists (grades 6-12) in which molecular scale mechanobiology is made more accessible through modern 3-D visualization. Such outreach will provide opportunities to reach underrepresented groups such as women and minorities and students in rural Pennsylvania, who visit Penn State frequently as they consider their higher education options.