CAREER: Virtual, high-throughput model of brain microvasculature regeneration

1150645Qutub，Amina该项目旨在开发一个强大的、创新的计算模型，用于研究微血管再生中的细胞事件，因为它们可能发生在大脑对缺氧的反应中。这项基础研究架起了理论生物学和临床应用之间的桥梁，并为缺血性中风和神经退行性疾病的修复机制提供了洞察力。影响美国5000多万人的疾病智力价值：关于神经血管界面的知识，即血管和脑细胞相遇的区域，为了解人类如何维持精神活动的能量、从缺血性脑损伤中恢复以及保护自己免受神经退化打开了大门。神经变性和脑缺血与缺氧反应和新血管的形成或血管生成有关。在这些疾病条件下，氧气的供应跟不上大脑的节奏？S需要。调节细胞缺氧反应和促进微血管生长是治疗缺血和减少神经变性的潜在途径。尽管它们有望成为治疗的靶点，但神经血管界面内的缺氧反应通路尚未得到很好的理解或详细的探索，无论是计算上还是实验上。在这个职业项目中，首席研究员(PI)将开发一个在低氧条件下形成脑微血管的模型。S项目的最终目标是建立一个详细的、量化的大脑微血管形成理论，它是由单个细胞所做决定的结果。为了达到它的目标，这项研究包括两个步骤：(1)表征神经血管细胞如何处理来自环境的信息；(2)将细胞行为模式与细胞内蛋白质信号联系起来。对细胞行为的假设将使用PI开发的新框架通过计算进行探索，并与体外测试进行迭代比较。细胞行为将通过采用高通量阵列技术的综合实验-计算方法映射到细胞内蛋白质的表达。结果会提供理解的能力吗？并最终制定计划？人类细胞在神经血管界面的行为。更广泛的影响：这项研究的影响横跨生物学、工程学和教育。细胞如何相互作用形成大脑毛细血管与生物体发育、哺乳动物合成生物学和组织工程有关。该项目将促进高通量分析与成像和蛋白质组分析相结合的开发，以及在细胞生物学、生物工程和药理学中的应用技术。皮？S计算机框架允许快速假设检验，可用于跨实验室和跨领域的研究。该项目还支持开发三种新的建模技术，这些技术可以广泛应用于研究作为分子信号功能的细胞行为模式。此外，这项工作产生的模型将能够模拟神经血管疾病中的血管再生，用于再生医学和基于蛋白质的药物开发。PI计划通过休斯顿社区、莱斯社区和国际上的扩展计划，通过开放源码网络技术，激发人们对不断增长的计算系统生物学领域的兴趣。PI将在她的实验室网站和模型库中向公众提供快速假设检验和3D成骨模型的计算机平台。用户友好的界面和iPhone应用程序将提供广泛的、免费的访问。世界各地的学生将能够在模型运行时与其互动，并学习计算系统生物学和微血管系统。这项技术将促进基于探究的教学，鼓励学生提出可验证的假设，并设计、运行和分析实验。与模特的培训将被整合到通过休斯顿健康博物馆为高中生组织的研讨会中，并开发一个本科生建模实验室。为了满足研究生和研究生对跨学科计算培训的需求，PI将发展她在墨西哥湾沿岸社区发起的复杂系统研讨会，并继续作为莱斯？S新系统与合成生物学项目的活跃核心成员。

1150645Qutub, AminaThis project seeks to develop a robust, innovative computational model of the cellular events in microvasculature regeneration as they might occur in the brain in response to hypoxia. This fundamental research bridges the gap between theoretical biology and clinical application, and offers insight into repair mechanisms for ischemic stroke and neurodegenerative diseases ? conditions affecting over 50 million people in the U.S.Intellectual Merit: Knowledge of the neurovasculature interface, the area where blood vessels and brain cells meet, opens doors to understanding how humans sustain energy for mental activities, recover from ischemic brain damage, and defend themselves from neurodegeneration. Neuro¬degen¬eration and brain ischemia are associated with hypoxic response and the formation of new blood vessels, or angiogenesis. In these disease conditions, the supply of oxygen does not keep pace with the brain?s needs. Regulating cellular hypoxic response and enhancing microvascular growth are potential ways to treat ischemia and minimize neurodegeneration. Despite their promise as a therapeutic target, hypoxia response pathways within the neuro¬vas¬culature interface have yet to be well understood or explored in detail, computationally or experimentally. In this CAREER project, the Principal Investigator (PI) will develop a model of brain microvasculature formation in hypoxia. The project?s ultimate goal is a mechanistically-detailed, quantitative theory of how brain microvasculature forms as a result of decisions made by single cells. To reach its goal, this research involves two steps: (1) characterizing how neurovascular cells process information from their environment; and (2) linking patterns in cell behaviors to intracellular protein signaling. Hypotheses for cell behaviors will be explored computationally using a new framework developed by the PI and iteratively compared to in vitro assays. Cell behaviors will be mapped to intracellular protein expression through an integrated experimental-computational approach employing high-throughput array technologies. Results will offer the ability to understand ? and ultimately program ? human cell behavior at the neurovascular interface. Broader Impacts: Impacts of this research span biology, engineering, and education. How cells interact to form brain capillaries has relevancy to organism development, mammalian synthetic biology, and tissue engineering. The project will foster the development of high-throughput assays coupled to imaging and proteomic analysis, technologies with applications in cell biology, bioengineering, and pharmacology. The PI?s computer framework allows rapid hypothesis testing, useable in research across labs and fields. The project also supports the development of three new modeling techniques that can be broadly applied to study patterns in cell behavior as a function of molecular signaling. Furthermore, models resulting from the work will be able to simulate vessel regeneration in neurovascular diseases for applications to regenerative medicine and protein-based drug development. The PI plans to stimulate interest in the growing field of computational systems biology through outreach programs in the Houston community, at Rice, and internationally, through open source web technology. The PI will provide the computer platform for rapid hypothesis testing and the 3D angi¬ogenesis models to the public, on her laboratory website and in model repositories. A user-friendly inter¬face and an iPhone App will give wide, free accessibility. Students worldwide will be able to interact with the model as it runs, and learn about computational systems biology and the microvasculature. This technology will foster inquiry-based teaching, where students will be encouraged to pose testable hypotheses, and design, run, and analyze experi¬ments. Training with the models will be inte¬grated into workshops for high school students organized through the Houston Health Museum and development of an undergraduate modeling lab. To fill the need for interdisciplinary computational training at the graduate and postgraduate level, the PI will grow the Complex Systems Workshops she initiated within the Gulf Coast community and remain an active, core member of Rice?s new Systems & Synthetic Biology program.