Decoding vomocytosis for cell-medaited, intra-lymph nodal delivery of microparticle vaccines

解码胞浆作用以实现细胞介导的微粒疫苗的淋巴结内递送

• 批准号: 9924928
• 负责人: Jamal S Lewis
• 金额: $ 5.88万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924928
• 关键词: Adaptive Immune System; Behavior; Biochemistry; Biocompatible Materials; Biological Process; Biophysics; Cell physiology; Cells; Cryptococcus neoformans; Cytoplasm; Dendritic Cells; Development; Disease; Drug Delivery Systems; Engineering; Environment; Enzymes; Exocytosis; Foundations; Goals; Immune; Immune system; Immunology; Immunotherapeutic agent; Infectious Agent; Instruction; Investigation; Laboratories; Lymph; Lymphatic; Lymphatic vessel; Mediating; Mission; Motivation; National Institute of General Medical Sciences; Nodal; Nonlytic; Organ; Particulate; Particulate Matter; Pathology; Peripheral; Phagocytes; Phagocytosis; Phagosomes; Prevention; Process; Reactive Oxygen Species; Reporting; Research; Research Support; System; Tissues; Vaccines; Vacuole; Vesicle; Work; Zika Virus; design; disease diagnosis; global health; health organization; immunoregulation; lymph nodes; macrophage; mimetics; multidisciplinary; next generation; novel; particle; programs; prophylactic; research and development; trafficking; uptake; vaccine delivery; vaccinology

DECODING VOMOCYTOSIS FOR CELL-MEDIATED, INTRA-LYMPH NODAL DELIVERY OF MICROPARTICLE VACCINES ABSTRACT/ SUMMARY The Immuno-modulatory Biomaterials Laboratory at UC Davis focuses on the development of novel biomaterial systems that can manipulate the immune system. Our goal is to design the next generation of immunotherapeutics for applications in immune-related diseases. This multidisciplinary work incorporates aspects of biomaterials engineering, drug delivery, immunology, biochemistry, and cell physiology. One of the main research programs in our lab is understanding controlled vomocytosis (non-lytic exocytosis) of particulate matter from phagocytic cells. Our primary motivation for elucidation of this process is the development of a `smart' microparticle system that can accomplish phagocytic cell-mediated delivery of vaccines directly to the lymph node-residing cells. Phagocytic cells (particularly macrophages [MΦ] and dendritic cells [DCs])) have evolved to circulate through peripheral tissue, engulf foreign particulate matter and traffick to the lymph node following uptake to relay information about the peripheral environment to cellular agents of the adaptive immune system. Evidently, phagocytic cells can transport particulate materials from peripheral tissues to lymphatic organs. Typically, following phagocytosis, and as phagocytic cells traverse the lymphatic vessels, materials that have been engulfed are taken into the phagosome (vacuole in the cytoplasm of a cell containing a phagocytosed particles) where a degradative process occurs due to secretion of reactive oxygen species (ROS), acidic pH and digestive enzymes. This stage would be counterproductive to the integrity of a particulate, and our purpose of intra-lymph nodal delivery. Moreover, release of particles from the phagocytic cell is not an intrinsic quality. But, there is precedent for such behavior. The fungal cell, Cryptococcus neoformans, elicits vomocytosis or (non-lytic exocytosis) from macrophages. There is still little understanding about the mechanisms governing this phenomena. Some reports indicate that there is an increase in pH of the phagosome during this activity, others have suggested Ca2+ flux could be pivotal for vesicle exocytosis. We believe that elucidation of the intra- phagosomal physico-chemical conditions that propel this activity could be instructive for the design of a mimetic microparticle. Further, investigation of the transcriptomal signatures between the period of phagocytosis and exocytosis could give us clues as to what biophysical factors are altered in the phagosome. Ultimately, our long- term goal is develop universally-deployable, microparticle vaccine platform as an effective, long-lasting prophylactic against infectious agents. The research and development of this platform system has the potential to significantly transform the treatment of a plethora of immune pathologies. Therefore, the proposed program is highly relevant to the mission of the National Institute of General Medical Sciences (NIGMS), which pertains to supporting research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention.

解码VOMOTOSIS用于细胞介导的微粒子疫苗的淋巴内递送 摘要/摘要 加州大学戴维斯分校免疫调节生物材料实验室专注于新型生物材料的开发 可以操纵免疫系统的生物材料系统。我们的目标是设计下一代 免疫治疗学在免疫相关疾病中的应用。这项多学科的工作包含了 生物材料工程、药物输送、免疫学、生物化学和细胞生理学。其中一个 我们实验室的主要研究项目是了解颗粒的受控呕吐(非溶血性胞吐)。 来自吞噬细胞的物质。我们解释这一过程的主要动机是开发一种“聪明的” 一种可实现吞噬细胞介导的疫苗直接输送到淋巴的微粒系统 驻留节点的单元。吞噬细胞(特别是巨噬细胞[MΦ]和树突状细胞[DC])已经进化到 在周围组织中循环，吞噬外来颗粒物，并在接下来的时间内流向淋巴结 摄取将有关周围环境的信息传递给适应性免疫系统的细胞代理。 显然，吞噬细胞可以将颗粒物质从周围组织输送到淋巴器官。 通常，在吞噬之后，当吞噬细胞穿过淋巴管时，具有 被吞噬的是被吞噬的小体(细胞质中的空泡，含有被吞噬的细胞 颗粒)，其中由于分泌活性氧物种(ROS)、酸性pH和 消化酶。这一阶段会对微粒的完整性产生反作用，而我们的目的是 在淋巴结内分娩。此外，从吞噬细胞释放颗粒不是一种固有的性质。但, 这种行为是有先例的。真菌细胞，新生隐球菌，引起呕吐或(非裂解) 从巨噬细胞中排出)。人们对这方面的管理机制仍知之甚少。 现象。一些报告表明，在这种活动过程中，吞噬小体的pH升高，其他的 提示Ca~(2+)通量可能在囊泡胞吐中起关键作用。我们认为，对内部- 促进这一活动的吞噬体物理化学条件可能对设计一种模拟物具有指导意义 微粒。此外，对吞噬阶段和吞噬阶段之间转录特征的研究 胞吐作用可以给我们提供线索，说明吞噬小体中的哪些生物物理因素发生了变化。最终，我们的长期- 长期目标是开发可普遍部署的微粒子疫苗平台，作为一个有效、持久的平台 预防感染性疾病的。该平台系统的研究和开发具有一定的潜力 以显著改变对过多免疫病理的治疗。因此，拟议的方案是 与国家普通医学科学研究所(NIGMS)的任务高度相关，该任务涉及 支持增加对生物过程的理解并为进步奠定基础的研究 在疾病诊断、治疗和预防方面。