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: 10216305
• 负责人: Jamal S Lewis
• 金额: $ 37.81万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216305
• 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; Mediating; Mission; Motivation; National Institute of General Medical Sciences; Nodal; Nonlytic; 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; lymphatic vessel; lymphoid organ; 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.

用于细胞介导的，淋巴的淋巴结液的呕吐作用，微颗粒疫苗的疫苗 摘要/摘要 加州大学戴维斯分校的免疫调节生物材料实验室的重点是新型的发展 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 用于免疫相关疾病应用的免疫治疗药。这项多学科的工作 生物材料工程，药物输送，免疫学，生物化学和细胞生理学方面的各个方面。中的一个 我们实验室中的主要研究计划是了解特定石的受控呕吐（非散囊胞吞） 来自吞噬细胞的物质。我们阐明这一过程的主要动机是开发“智能” 可以直接完成吞噬细胞介导的疫苗递送到淋巴的微粒系统 节点保留细胞。吞噬细胞（尤其是巨噬细胞[Mφ]和树突状细胞[DCS]）已经演变为 通过外周组织，吞噬外来特定物质和淋巴结的流量 接收有关外围环境的信息到自适应免疫系统的细胞剂。 显然，吞噬细胞可以将特定材料从外周组织运输到淋巴器官。 通常，吞噬作用和吞噬细胞遍历淋巴管，具有 他们被吞噬被吞噬成吞噬体（液泡在包含吞噬细胞的细胞的细胞质中 粒子）由于活性氧（ROS），酸性pH和 消化酶。这个阶段将对特定的完整性适得其反，我们的目的 淋巴结内递送。此外，从吞噬细胞中释放颗粒不是固有的质量。但， 这种行为有先例。真菌细胞，加密环球机构，引起呕吐或（非lytict） 巨噬细胞的胞吞作用）。对此的机制仍然很少了解 现象。一些报告表明，在此活动期间，吞噬体的pH值有所增加，另一些则 已经建议Ca2+通量可能是蔬菜胞吐作用的关键。我们认为阐明内部 推动此活动的吞噬体物理化学条件可能对模仿的设计具有启发性 微粒。此外，研究吞噬时期和 胞吐作用可以为我们提供有关吞噬体中哪些生物物理因子的线索。最终，我们的长期 术语目标是普遍开发的，可普遍使用的微粒疫苗平台，作为一种有效的，持久的 预防性对传染剂的预防性。该平台系统的研究和开发具有潜力 显着转化了多种免疫病理的治疗。因此，拟议的程序是 与国家一般医学科学研究所（NIGMS）的任务高度相关，该任务与 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，治疗和预防中。