This 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.
