Designing supramolecular delivery strategies to understand and exploit synergies in immunoregenerative medicine

摘要 目前尚不清楚为什么一些组织损伤会再生并愈合，而另一些组织损伤会形成纤维和疤痕。很明显， 然而，炎症反应是这些不同结果的基础。这种免疫系统的反应 损伤依赖于多种细胞类型和器官系统，这些细胞类型和器官系统仍在交流中进化 总体而言，指导组织水平的结果。我的实验室的专长是设计当地的药物输送系统 免疫调节。我们将利用这些交付平台来探索局部免疫系统的相互作用 治疗交付，应用于组织愈合和阻止炎症性疾病的进展。 主题1：治疗药物的细胞靶向传递如何改变单核细胞和巨噬细胞的串扰？ 巨噬细胞是先天免疫系统的主要组成部分，对损伤和 启动其他细胞类型的激活--包括用从 骨髓。促进促再生的巨噬细胞表型是一条有希望的治疗途径 广泛的调查。然而，巨噬细胞极化如何改变单核细胞却知之甚少。 招聘和差异化。这个项目领域是基于我在治疗巨噬细胞极化方面的经验。 为了开发细胞靶向疗法，促进损伤部位促进愈合的巨噬细胞表型， 探索改变单核细胞募集和分化的假说，而不是持久的一代 促进愈合的巨噬细胞是支持免疫再生反应的关键轴。主题2：如何 促进早期损伤后炎症改变获得性免疫反应？震级和 细胞信号的时间序列，包括趋化因子和细胞因子，是细胞迁移的关键调节因子， 分化和极化；这些过程指导损伤免疫微环境的演变和 由此产生的组织水平的结果。最近观察到，外源性传递炎症信号 促进缺血损伤后的组织愈合。在这里，我们将探索有益效果产生的假设 通过巨噬细胞衍生的信号对调节性T细胞的募集和分化，这可以被重新激活。 通过从可注射水凝胶中顺序释放生物分子而屈服。如果成功，这个项目将阐明 引导损伤免疫微环境向功能方向发展的新设计原则 支持组织愈合。主题3：远程药物输送系统能否调节破坏性的全身系统 发炎？调节失调的全身性炎症的后遗症通常是由显著的组织侮辱引起的 (心脏病发作、肾脏损伤)或慢性炎症性疾病(炎症性肠炎、类风湿性关节炎)。是这样的 侮辱与有害的多器官效应有关，包括肾和肺纤维化， 动脉粥样硬化和心力衰竭。这一研究领域探索开发可再灌装的药物储藏库的能力。 用于将免疫调节药物输送到远处的免疫器官，从而调节 主要细胞来源。

ABSTRACT It remains unclear why some tissue injuries regenerate and heal while others fibrose and scar. It is evident, however, that the inflammatory response underlies these divergent outcomes. This immune system’s response to injury depends on a multitude of cell types and organ systems that remain in communication to evolve collectively, guiding tissue-level outcomes. My lab’s expertise is in the design of local drug delivery systems for immune modulation. We will leverage these delivery platforms to explore immune systems interactions after local therapeutic delivery, with applications toward tissue healing and arresting inflammatory disease progression. Theme 1: How does cell-targeted delivery of therapeutics alter monocyte & macrophage crosstalk? Macrophages are a primary component of the innate immune system, acting as first-responders to injury and initiating the activation of other cell types – including their replacement by monocyte precursors recruited from the bone marrow. Promoting a pro-regenerative macrophage phenotype is a promising therapeutic avenue under widespread investigation. However, little is known about how macrophage polarization alters monocyte recruitment and differentiation. This project area builds on my experience in therapeutic macrophage polarization to develop cell-targeted therapeutics that promote a pro-healing macrophage phenotype at the injury site, exploring the hypothesis that altered monocyte recruitment and differentiation, not the long-lasting generation of pro-healing macrophages, is the critical axis supporting an immunoregenerative response. Theme 2: How does the promotion of early post-injury inflammation alter adaptive immune response? The magnitude and temporal sequence of cell signals, including chemokines and cytokines, is a critical regulator of cell migration, differentiation, and polarization; these processes guide evolution of the injury immune microenvironment and resulting tissue-level outcomes. It has been recently observed that exogenous delivery of inflammatory signaling promotes tissue healing after ischemic injury. Here, we will explore the hypothesis that beneficial effects result from the recruitment and differentiation of regulatory T cells by macrophage-derived signals, which can be re- capitulated by sequential biomolecule release from injectable hydrogels. If successful, this project will elucidate new design principles for guiding the injury immune microenvironment toward a functional orientation that supports tissue healing. Theme 3: Can remote drug delivery systems modulate damaging systemic inflammation? A sequela of dysregulated systemic inflammation often results from significant tissue insults (heart attack, kidney injury) or chronic inflammatory disease (inflammatory bowel, rheumatoid arthritis). Such insults are associated with deleterious multi-organ effects, including renal and pulmonary fibrosis, atherosclerosis, and heart failure. This area of research explores the capacity to develop refillable drug reservoirs for delivering immunomodulatory drugs to distant immune organs, thereby modulating inflammation at the primary cell sources.