CAREER: Engineered Hydrogels to Study Host-Parasite Interactions that Drive Extracellular Matrix Remodeling

当某些寄生虫侵入我们的身体时，它们通常会导致一种奇怪的现象——内脏变大。在利什曼原虫感染中，即使在患者清除了寄生虫后，由于肝脏组织结构的重大变化，肝脏仍保持扩大。该项目旨在揭示这些寄生虫如何引起肝细胞外基质（ECM）的变化，ECM是包围和支持细胞的组织成分。这一探索的核心是肝星状细胞（hsc），它是协调肝脏ECM构建的关键架构师。研究人员假设利什曼原虫操纵这些细胞，引起ECM的修饰和肝脏大小的增加。为了验证这一假设，研究人员将使用模仿人体ECM的材料来培养造血干细胞，并在实验室中创建微型组织模型。然后，研究小组将使用这些模型来研究造血干细胞在利什曼原虫感染后的行为，并检查它们与巨噬细胞的相互作用——巨噬细胞是这些寄生虫的首选宿主。同时，受这些研究思路的启发，研究者将为拉丁中学生创建一个组织工程研讨会，为注册“生物医学工程全球健康”的研究生实施国际虚拟交流，并使用钩针编织SciArt和社交媒体告知人们这些和其他热带寄生虫日益增加的危险。器官肿大是慢性原虫感染的常见现象。利什曼原虫亚属的原生动物引起肝脏的严重肿胀。清除寄生虫后肝脏继续扩大，并与宿主细胞外基质（ECM）的广泛修饰有关。这些寄生虫诱导ECM重塑的生物学过程尚不清楚。由于肝星状细胞（hsc）是肝脏中ECM产生的主要驱动因素，因此本项目的中心假设是利什曼原虫感染通过激活hsc诱导ECM重塑。考虑到巨噬细胞是利什曼原虫的主要常驻细胞，第二种假设是感染的巨噬细胞也介导造血干细胞的激活。使用传统的体外系统测试这些假设是不可能的，因为在组织培养聚苯乙烯上培养会导致星状细胞的自发激活。此外，大多数利什曼原虫体外模型研究的是在不能考虑宿主ECM特征的环境中培养的单一宿主细胞类型。研究者将通过利用生物材料来设计改进的体外模型来解决这些问题，以解决以下研究目标：(1)设计一种支持静止HSC培养的生物材料，(2)评估感染多诺瓦利什曼原虫后HSC的激活和ECM的产生，(3)评估与感染利什曼原虫的巨噬细胞或其释放的细胞外囊泡共培养后HSC的表型。因此，该提案将利用工程和生物材料策略来解决我们对宿主-寄生虫相互作用的理解中的关键空白。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

When certain parasites invade our bodies, they often lead to a peculiar thing – internal organs get larger. In Leishmania infections, even after patients clear out the parasites, the liver stays enlarged due to substantial changes in its tissue structure. This project aims to uncover how these parasites cause changes in the liver extracellular matrix (ECM) – the tissue components that surround and support cells. At the core of this exploration are hepatic stellate cells (HSCs), pivotal architects orchestrating the construction of liver ECM. The investigators hypothesize that Leishmania manipulates these cells, instigating modifications to the ECM and an increase in liver size. To test this hypothesis, the investigators will employ materials that mimic the ECM in human bodies to culture HSCs and create mini tissue models in the laboratory. The team will then use these models to study how HSCs behave after Leishmania infection and examine their interactions with macrophages – immune cells that are the preferred host for these parasites. Inspired by these research ideas, in parallel, the investigator will create a tissue engineering workshop for Latine middle-school students, implement an international virtual exchange for graduate students enrolled in “Global Health in Biomedical Engineering." and use crocheted SciArt and social media to inform people about the increasing dangers of these and other tropical parasites.Organ enlargement is a common phenomenon observed in chronic protozoal infections. Protozoa of the Leishmania subgenus cause substantial swelling of the liver. Liver enlargement persists after parasite clearing and is linked to extensive modifications of host extracellular matrix (ECM). The biological processes through which these parasites induce ECM remodeling is not well understood. Because hepatic stellate cells (HSCs) are the dominant drivers of ECM production in the liver, the central hypothesis of this project is that Leishmania infection induces ECM remodeling through the activation of HSCs. Considering macrophages are the primary resident cell for Leishmania, a secondary hypothesis is that infected macrophages also mediate the activation of HSCs. Testing these hypotheses is not possible using traditional in vitro systems because culture on tissue culture polystyrene leads to the spontaneous activation of stellate cells. Furthermore, most Leishmania in vitro models study a single host cell type cultured in environments that fail to account for the characteristics of host ECM. The investigator will address these concerns by leveraging biomaterials to engineer improved in vitro models that address the following research objectives: (1) design a biomaterial that supports the culture of quiescent HSCs, (2) assess HSC activation and ECM production after infection with Leishmania donovani, and (3) evaluate HSC phenotype after co-culture with Leishmania-infected macrophages or their released extracellular vesicles. Thus, this proposal will leverage engineering and biomaterials strategies to address critical gaps in our understanding of host-parasite interactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.