BRIGE: Engineering Functional Human Microvessels for Studying Microvascular Permeability

PI：刘，宇信命题编号：1227359智慧价值巨噬细胞可被经典激活或交替激活，分别产生促炎或促血管生成分子。肿瘤相关巨噬细胞(TAMs)是促进肿瘤生长的交替激活细胞。TAMs可以通过将药物输送到经典激活的巨噬细胞来重新编程，巨噬细胞可以杀死肿瘤细胞。对TAMS的歧视性给药提供了一种非常有吸引力的癌症治疗方法，其中激活的巨噬细胞可以被修复以摧毁恶性细胞。因此，我们的长期目标是有区别地向TAMs提供促进肿瘤消退的药物。这项提议的目标是确定什么表面属性允许选择性靶向交替激活的巨噬细胞，这是追求这一目标的下一步。这一建议的理论是，针对TAMs的歧视性靶向可以通过工程微粒组合物来实现，从而优先增强交替激活的巨噬细胞的吞噬作用。这项拟议研究的基本原理是，一旦知道什么材料参数影响交替激活的巨噬细胞的选择性吞噬作用，就会发现设计抗癌疗法的新的创新策略。这一假说将通过以下目的得到验证：目的1)确定哪些微粒子的性质有助于在活体中进行选择性吞噬2)工程聚合物系统以确定选择性地向TAM递送重编程药物的最佳条件拟议的研究有望有助于深入了解如何最好地设计药物递送载体，从而使TAM能够被重新编程以摧毁癌细胞。这项工作将产生关于什么聚合物参数和颗粒配置增加药物向巨噬细胞输送的信息。这一贡献意义重大，因为它有望通过利用聚合物特性和颗粒组成来区别对待TAMs，从而产生对肿瘤有毒的分子，从而彻底改变抗癌药物的输送方式。更广泛的影响开发新的抗癌疗法将对癌症患者产生巨大影响。此外，这项研究有望改善有关如何最好地设计药物输送载体以靶向或激活的巨噬细胞的知识。这有可能对心血管疾病患者、接受抗逆转录病毒治疗的患者和自身免疫性疾病患者产生积极影响。这项研究和其中包含的目标是积极让从高中到研究生的学生参与实验室的理想选择。通过与妇女参与科学和工程计划(PWSE)的合作，将向高中女孩介绍这项研究。此外，目前正在从事这一项目的一名本科生已通过PWSE计划招聘。我们生活在一个无线世界，在这个世界里，大量的通信都是数字化的。为了充分利用这个现代世界，这项提案中所做的研究，以及从文献中获得的知识，将结合在一起，形成一款iPad/iPhone应用程序。这款应用程序将把通过这项研究收集到的知识传播给所有类型的学生，并可能对国家/世界上这些类型的课程和专业人员难以获得的地区的学生产生特别的影响。

PI: Liu, YuxinProposal Number: 1227359Intellectual MeritMacrophages can be activated classically or alternatively to produce pro-inflammatory or pro-angiogenic molecules, respectively. Tumor associated macrophages (TAMs) are alternatively activated cells that promote tumor growth. TAMs can be reprogrammed through drug delivery to classically activated macrophages, which kill neoplastic cells. Discriminatory drug delivery to TAMs presents a very attractive cancer therapeutic in which alternatively activated macrophages could be reconditioned to destroy malignant cells. Therefore, our long term goal is to deliver drugs discriminately to TAMs that will promote tumor regression. The objective of this proposal, which is the next step in pursuit of that goal, is to determine what surface properties allow for selective targeting to alternatively activated macrophages. This proposal theorizes that discriminatory targeting to TAMs can be achieved through engineering microparticle compositions such that phagocytosis is preferentially enhanced in alternatively activated macrophages. The rationale for the proposed research is that, once it is known what material parameters influence selective phagocytosis in alternatively activated macrophages, new and innovative strategies for designing anti-cancer therapeutics will be uncovered. This hypothesis will be tested through the following aims:Aim 1) Determine what microparticle properties result in the facilitation of selective phagocytosis in vivoAim 2) Engineer polymeric systems to determine the best conditions for selectively delivering reprogramming drugs to TAMsThe proposed research is expected to contribute in-depth understanding of how best to engineer the drug delivery vehicle such that TAMs are reprogrammed to destroy cancerous cells. This work will generate information on what polymer parameters and particle configurations augment drug delivery to macrophages. This contribution is significant, because it is expected to revolutionize anti-cancer drug delivery through exploiting polymer properties and particle compositions to discriminately target TAMs, such that they produce molecules that are toxic to tumors. Broader ImpactsDeveloping novel anti-cancer therapeutics will have a tremendous impact on cancer patients. In addition, this research is expected to be able to improve knowledge pertaining to how to best engineer a drug delivery vehicle to target alternatively activated macrophages. This has the potential to positively impact people stricken with cardiovascular disease, people on antiretroviral therapy, and patients with autoimmune diseases. This research and the goals contained within are ideal for actively involving student's from high school to graduate student's in the lab. Through collaboration with the Program for Women in Science and Engineering (PWSE), high school girls will be introduced to this research. In addition, an undergraduate currently working on this project has been recruited through the PWSE program. We live in a wireless world in which large amount of communications are digital. To take full advantage of this modern world, the research done in this proposal, along with the knowledge obtained from the literature, will be combined to form an iPad/iPhone app. This app will disseminate the knowledge gleaned through this study to all types of students, and may be particularly impactful for students in areas of the country/world in which these sorts of classes and professionals are not readily available.