CAREER: The Landscape of Differentiation: Understanding the Mesenchymal Stem Cell Response to the Topography and Geometry of their Environment

这项研究的目标是利用数学模型和实验，从因果机制上理解骨髓基质细胞(MSCs)对其培养表面的表面形貌的反应。虽然主要关注的是间充质干细胞，但许多正在解决的问题与其他哺乳动物细胞相关。将建立细胞在光滑表面和纳米图案表面上的扩散、黏附和细胞形状的理论模型。将建立计算机信号模型，揭示细胞形状和MSCs分化决策之间的联系。合作实验室的实验将有助于模型开发和模型验证。该项目将有助于了解组织本身的物理属性如何通过调节多能干细胞的分化决定来影响组织维持(或内稳态)。这可能是细胞外基质帮助塑造组织的过程。目前对这些过程缺乏了解，这项研究试图帮助填补这一空白。该项目将通过开发不同环境中细胞的生物物理模型来对组织的动态平衡和发育产生新的见解，该模型集成了环境、细胞骨架和信号之间的相互作用和反馈。该研究计划为培养研究生、本科生、在校学生和K-12教师提供支持。PI的主要教育目标是向从在校学生到研究生的不同层次的学生教授和传播生物学和生态学的建模方法。PI将开发一门关于生物学建模方法的本科课程，并将他的实验室进行的研究以及来自世界各地的当前研究纳入教学大纲。除了在他的实验室培训研究生外，PI还将为本科生和即将入学的新生，特别是来自代表性不足的少数族裔的学生，提供参加暑期研究的机会。与CSU自然科学学院教育和推广中心(EOC-CNS)合作，PI将开发课程材料并举办讲习班，培训K-12教师使用免费在线工具(如NetLOGO)建立计算模型以理解复杂生物和生态现象的艺术和科学。这也将适用于EOC-CNS目前参与的正在进行的K-12项目。EoC-CNS将帮助设计讲习班，招聘教师，特别是那些教授代表性不足的少数群体的教师，并将由专业评估员帮助评估讲习班的影响。参加讲习班的K-12教师将接受培训，以便将计算模型纳入他们的教学以及学校的研究活动。在柯林斯堡学校组织的夏季STEM夏令营期间，还将与K12教师合作，直接向学校学生提供讲习班。重点将是利用Netlogo等建模工具来制作和可视化简单的模型，这些模型可以洞察复杂的现象，涉及非线性、随机性、反馈和同步。课程将以生态学和生物学为例，特别是关于K-12学生在课堂上会遇到的建模现象。

The goal of this research project is to develop a causal mechanistic understanding of the response of bone marrow stromal cells (MSCs) to the topography of the surfaces that they are cultured on, utilizing mathematical models and experiments. While the primary focus is on MSCs, many of the questions being addressed are relevant to other mammalian cells. Theoretical models will be developed of cell spreading, adhesion and cell shape on smooth surfaces and on nano-patterned surfaces. Computational signaling models will be built that uncovers the linkages between cell shape and the differentiation decision of MSCs. Experiments in collaborating laboratories will facilitate model development and model validation.The project will help understand how the physical properties of the tissues themselves affect tissue maintenance (or homeostasis) through modulation of the differentiation decision of multipotent stem cells. This may be the process by means of which the extra-cellular matrix helps shape tissues. An understanding of these processes is currently lacking, and this research seeks to help fill this gap. The project will yield new insights into tissue homeostasis and development via the development of biophysical models of cells in different environments, which integrates the interactions and the feedback between the environment, the cellular cytoskeleton and signaling. The research program offers support for training graduate students, undergraduate students, school students and K-12 teachers. The main educational goal of the PI is teaching and disseminating modeling methods for biology and ecology to students at different levels, from school students to graduate students. The PI will develop an undergraduate-level course on modeling methods in biology, and incorporate research carried out in his laboratory, as well as current research from the world over, in the syllabus. Apart from training graduate students in his laboratory, the PI will offer undergraduate students and incoming freshmen, especially students from underrepresented minorities, an opportunity to participate in summer research. In collaboration with the Education and Outreach Center of the College of Natural Sciences (EOC-CNS) at CSU, the PI will develop course material and hold workshops to train K-12 teachers in the art and science of building computational models to understand complex biological and ecological phenomena using free online tools such as Netlogo. This will also be applied to ongoing K-12 projects that the EOC-CNS is currently involved. The EOC-CNS will help design the workshops, recruit teachers especially those who teach under-represented minorities, and will also help evaluate the impact of the workshops by a professional evaluator. K-12 teachers attending the workshop will be trained to incorporate computational models into their teaching, as well as into school research activity. Workshops will also be offered directly to school students, in collaboration with K12 teachers, during summer STEM camps organized by schools in Fort Collins. The emphasis will be on exploiting modeling tools such as Netlogo to make and visualize simple models that give insight into complicated phenomena, involving nonlinearity, stochasticity, feedback and synchronization. Examples will be taken from ecology and biology, and especially on modeling phenomena that K-12 students will encounter in their classes.