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

职业：脑微血管再生的虚拟高通量模型

• 批准号: 1150645
• 负责人: Amina Qutub
• 金额: $ 43.51万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1150645&HistoricalAwards=false
• 关键词: CAREER; Virtual; throughput; model; brain

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.

1150645 Qutub，Amina该项目旨在开发一个强大的，创新的微血管再生细胞事件的计算模型，因为它们可能发生在大脑中对缺氧的反应。 这一基础研究弥合了理论生物学和临床应用之间的差距，并提供了深入了解缺血性中风和神经退行性疾病的修复机制？智力优势：神经血管接口的知识，血管和脑细胞相遇的区域，打开了理解人类如何维持精神活动的能量，从缺血性脑损伤中恢复，并保护自己免受神经退行性疾病的大门。 神经变性和脑缺血与缺氧反应和新血管形成或血管生成相关。 在这些疾病的条件下，氧气的供应跟不上大脑的速度？s的需要。 调节细胞缺氧反应和促进微血管生长是治疗缺血和最小化神经变性的潜在途径。 尽管它们有望作为治疗靶点，但神经血管界面内的缺氧反应途径尚未被很好地理解或详细地、计算地或实验地探索。 在本CAREER项目中，主要研究者（PI）将开发缺氧条件下脑微血管形成的模型。 项目？的最终目标是一个详细的，定量的理论，大脑微血管系统如何形成的结果，由单细胞的决定。 为了实现其目标，这项研究涉及两个步骤：（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。 将使用PI开发的新框架通过计算探索细胞行为的假设，并与体外试验进行迭代比较。 细胞行为将映射到细胞内的蛋白质表达，通过一个综合的实验-计算的方法，采用高通量阵列技术。 结果将提供理解的能力？最终，方案？人类细胞在神经血管界面的行为。 更广泛的影响：这项研究的影响跨越生物学，工程学和教育。 细胞如何相互作用以形成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。 该项目将促进与成像和蛋白质组学分析相结合的高通量测定的发展，这些技术在细胞生物学，生物工程和药理学中具有应用。 私家侦探？的计算机框架允许快速的假设检验，可用于跨实验室和领域的研究。 该项目还支持开发三种新的建模技术，这些技术可广泛应用于研究细胞行为模式作为分子信号的功能。 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，赖斯和国际上的外展计划，通过开源网络技术，激发人们对不断增长的计算系统生物学领域的兴趣。 PI将在其实验室网站和模型库中向公众提供用于快速假设检验和3D血管生成模型的计算机平台。 用户友好的界面和iPhone应用程序将提供广泛的免费访问。 世界各地的学生将能够在模型运行时与模型进行交互，并了解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，鼓励学生提出可检验的假设，并设计、运行和分析实验。 这些模型的培训将被纳入休斯顿健康博物馆为高中生组织的研讨会，并开发一个本科生建模实验室。 为了满足研究生和研究生阶段跨学科计算培训的需求，PI将在墨西哥湾沿岸社区内建立她发起的复杂系统研讨会，并继续成为Rice的活跃核心成员。新的系统合成生物学计划。