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

摘要 目前还不清楚为什么有些组织损伤再生和愈合，而其他纤维化和疤痕。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 损伤依赖于大量的细胞类型和器官系统，这些系统保持着进化的联系。 共同指导组织水平的结果。我实验室的专长是设计局部给药系统 免疫调节我们将利用这些交付平台来探索局部免疫后免疫系统的相互作用。 治疗递送，用于组织愈合和阻止炎性疾病进展。 主题1：治疗药物的细胞靶向递送如何改变单核细胞和巨噬细胞的相互作用？ 巨噬细胞是先天免疫系统的主要组成部分，作为损伤的第一反应者， 启动其他细胞类型的激活-包括它们被从单核细胞中募集的单核细胞前体替代， 骨髓促进促再生巨噬细胞表型是一种有前途的治疗途径， 广泛的调查。然而，关于巨噬细胞极化如何改变单核细胞， 招聘和分化。这个项目领域建立在我的治疗巨噬细胞极化的经验 为了开发在损伤部位促进促愈合巨噬细胞表型的细胞靶向治疗剂， 探索改变单核细胞募集和分化的假设，而不是单核细胞的长期生成。 促愈合巨噬细胞是支持免疫反应的关键轴。主题二：如何 促进损伤后早期炎症改变适应性免疫反应？的幅度和 包括趋化因子和细胞因子在内的细胞信号的时间序列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进化， 从而产生组织水平的结果。最近已经观察到，炎症信号的外源性递送 促进缺血性损伤后的组织愈合。在这里，我们将探讨的假设，有益的影响， 从巨噬细胞来源的信号的调节性T细胞的募集和分化，这可以重新 通过从可注射水凝胶中连续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：远程给药系统能否调节损伤性系统性疾病 炎症？系统性炎症失调的后遗症通常是由严重的组织损伤引起的 （心脏病发作、肾损伤）或慢性炎症性疾病（炎症性肠病、类风湿性关节炎）。等 损伤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填充药物储存器的能力 用于将免疫调节药物递送至远端免疫器官，从而调节免疫器官处的炎症。 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.