BRIGE: Engineering Functional Human Microvessels for Studying Microvascular Permeability

BRIGE：工程功能性人体微血管用于研究微血管渗透性

• 批准号: 1227359
• 负责人: Yuxin Liu
• 金额: $ 17.5万
• 依托单位: West Virginia University Research Corporation
• 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: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1227359&HistoricalAwards=false
• 关键词: BRIGE; Engineering; Functional; Human; Microvessels

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.

主要研究者：刘宇新提案编号：1227359智力优点巨噬细胞可以被经典地或替代地激活，分别产生促炎症或促血管生成分子。肿瘤相关巨噬细胞（TAM）是促进肿瘤生长的交替活化细胞。TAM可以通过药物递送重新编程为经典活化的巨噬细胞，其杀死肿瘤细胞。区别性药物递送到TAM呈现出非常有吸引力的癌症治疗，其中可替代地活化的巨噬细胞可以被修复以破坏恶性细胞。因此，我们的长期目标是有区别地将药物递送到将促进肿瘤消退的TAM。该提案的目的是追求该目标的下一步，是确定什么样的表面特性允许选择性靶向替代活化的巨噬细胞。该提议从理论上证明，可以通过工程化微粒组合物来实现对TAM的区分性靶向，使得吞噬作用在交替活化的巨噬细胞中优先增强。这项研究的基本原理是，一旦知道什么材料参数会影响选择性激活的巨噬细胞的吞噬作用，就可以发现设计抗癌疗法的新的创新策略。这一假设将通过以下目标进行测试：目标1）确定什么微粒特性导致体内选择性吞噬的促进目标2）工程聚合物系统，以确定选择性地将重编程药物递送到TAM的最佳条件拟议的研究预计将有助于深入了解如何最好地工程药物递送载体，使TAM被重编程以破坏癌细胞。这项工作将产生什么样的聚合物参数和颗粒配置增强药物输送到巨噬细胞的信息。这一贡献是重要的，因为它有望通过利用聚合物性质和颗粒组成来彻底改变抗癌药物递送，以区别性地靶向TAM，使得它们产生对肿瘤有毒的分子。更广泛的影响开发新的抗癌疗法将对癌症患者产生巨大的影响。此外，这项研究预计能够提高有关如何最好地设计药物递送载体以靶向替代活化的巨噬细胞的知识。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理想的积极参与学生从高中到研究生的实验室。通过与科学和工程妇女方案（PWSE）的合作，将向高中女生介绍这项研究。此外，目前正在从事该项目的一名本科生已通过PWSE计划招募。 我们生活在一个无线的世界，其中大量的通信是数字的。为了充分利用这个现代化的世界，本提案中所做的研究，沿着从文献中获得的知识，将结合形成一个iPad/iPhone应用程序。该应用程序将向所有类型的学生传播通过本研究收集的知识，并可能对这些课程和专业人员不容易获得的国家/世界地区的学生产生特别的影响。