Modeling of Pathological and Developmental Angiogenesis
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: ABSTRACT Blood vessel formation requires an elaborate coordination between cell proliferation, migration, differentiation, and heterotypic cell-cell interactions. The process is essential to mammalian development and plays a critical role in homeostasis, tissue / organ repair, and in the outcome of many pathologies. In fact, modulation of the angiogenic response has been a targeted area for therapeutic interventions in cancer, retinopathies, arthritis, cardiac disease and a large number of skin disorders. Although these therapies have shown remarkable success in some patients, there is significant heterogeneity in response and efficacy. This lack of predictability in the individual response of patients has diluted the benefit and effectiveness. Along these lines, there is urgent need for technology to assess vascular responses to a particular therapy. The central hypothesis of this application is that the development of angiogenic modeling algorithms will significantly aid in predicting the effectiveness of a particular angiogenic therapy based on tissue-specific and signaling-specific parameters. Once generated, the technology could also be applied to the development of biocompatible materials for tissue transplantation specifically in the design of vascular patterns that best fulfill the physiological needs of individual organs. To test our hypothesis, we have gathered a strong interdisciplinary group from UCLA and LANL investigators who will tackle distinct aspects of this problem according to their strengths and expertise. These individuals have a track record of collaborations and focal interests, however never had the opportunity to join their abilities towards the accomplishment of common goal. Through this proposal, these investigators will provide complementary expertise to achieve a central objective: the development of comprehensive modeling programs to predict vascular growth. An important advantage of the experimental design presented in this proposal is that it will be accomplished by graduate students. They will spend equivalent amounts of time in the laboratories of each investigator, as per the demands of their specific projects. Consequently, each student will interact with all three investigators of the research team, enabling comprehensive interdisciplinary training and interactions. The technology to be developed will require students to use and generate sophisticated transgenic models (Dr. Tim Lane’s expertise), acquire data on vascular growth using multiphoton real-time confocal imaging; gain understanding of cell signaling of blood vessels for interpretation of their data (Dr. Iruela-Arispe’s expertise), and develop computer algorithms to generate modeling programs (Dr. Yi Jiang’s expertise). Each of the three students to be recruited will focus on specific tasks: (1) modeling developmental angiogenesis; (2) modeling tumor angiogenesis; (3) modeling tumor angiogenesis during therapeutic intervention. These are the three specific aims of the proposal. Because the work-frame of tasks is similar students will learn from each other and will also be able to cross-compare their results. The team will meet once per year to assess progress and discuss future directions. At the end of first yeas, we expect to have developed a strong framework of computer modeling programs that mimic developmental and pathological vascular growth. The validation of the modeling programs will be performed during years 2 and 3 by experimental testing using in vivo systems. Modulation of parameters, such as growth factor signaling (using transgenics) will aid in further assessment of the algorithms generated. The inclusion of the therapeutic aim will test the value of the computer modeling parameters for medical application during anti-angiogenic intervention. Considering that the large majority of the transgenic models and cutting-edge imaging technology already at hand, we anticipate that the execution of the proposal will not be hindered by road-blocks associated with development of reagents. Furthermore, there is a cohort of 8 students within the laboratories of the UCLA members of the team who are interested in participating in this project already. Thus, we anticipate that this might become a successful and rather unique program. The impact of this research has potential to aid, in a meaningful manner, the testing of current angiogenic therapies and the design of vascular patterns in biocompatible tissues for organ transplantation.