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Tissue repair, extracellular vesicular biogenesis, and the control of immune responses

组织修复、细胞外囊泡生物发生和免疫反应的控制

基本信息

批准号：
10646318
负责人：
Brian P Eliceiri
金额：
$ 37.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646318
关键词：
Acceleration Address Adoptive Transfer Affect Animal Model Autologous Biogenesis Biological Biological Response Modifiers Cell secretion Cells Complement Environment Excision Family Flow Cytometry Gene Delivery Goals Human Immune Immune response Immunocompetent Immunodeficient Mouse Immunologic Deficiency Syndromes Impaired wound healing Implant In Vitro Inflammation Intercellular Communication Process Kinetics Knockout Mice Liquid substance Location Mediating Mediator Monomeric GTP-Binding Proteins Mus Mutant Strains Mice Nucleic Acids Pathway interactions Phase Population Porifera Process Proteins Resolution Role Signal Transduction Site Skin Skin injury Skin repair Skin wound healing Source Surface Testing Therapeutic Thick Time Vesicle Xenograft procedure cell type diabetic extracellular extracellular vesicles genetic approach immune activation in vivo insight intercellular communication interdisciplinary approach knock-down member mouse model overexpression patient derived xenograft model programs recruit repaired skin wound subcutaneous tissue repair vesicular release wound wound bed wound closure wound healing

项目摘要

SUMMARY Resolution in skin wound healing is coordinated by intercellular communication processes that include extracellular vesicles (EVs) containing biologically active protein and nucleic acid. While EV biogenesis has been studied in vitro, systematic approaches to identify their in vivo relevance are limited. Having established that the expression of TBC/RabGAPs controls EV biogenesis and ‘re-programs’ EV content to uncouple the pro-reparative activities of EVs in inflammation, we propose to use a genetic approach to target the secretory machinery implicated in EV biogenesis (i.e. Rabs 5, 11, and 27A) to determine how these targets of TBC/RabGAPs regulate the payload of EVs. We will determine how EVs, and changes in EVs, impact the resolution of inflammation, and gain insight into the role of EVs in wound healing. In Aim 1, we will use vesicle flow cytometry to define EV subsets, followed by adoptive transfer of EVs to determine their capacity to activate specific immune cell populations in diabetic and immunodeficient knockout mouse models that mediate cutaneous wound closure. Aim 2 will study specific Rabs to determine how these Rabs impact EV biogenesis and content. In addition, using the EVs formed in the altered Rab environment, we will establish the mechanism of action and effect of these EVs on the kinetics of resolution of specific immune responses. Together, these studies will establish the relevance of EVs as potential therapeutics and address the over-arching goal of systematically creating therapeutic EVs that are specifically optimized for specific phases of skin repair.

摘要皮肤伤口愈合中的解决方案是通过细胞间通讯过程协调的，包括含有生物活性蛋白质和核酸的胞外小泡(EV)。而当 EV的生物发生已经在体外进行了研究，系统地确定了它们在体内的相关性是有限的。已经确定TBC/RabGAPs的表达控制EV的生物发生和 RE-Program的EV内容为了在炎症中解偶联EV的促修复活性，我们建议使用遗传方法来针对EV生物发生所涉及的分泌机制 (即RAB 5、11和27A)，以确定TBC/RabGAP的这些目标如何调节有效载荷电动汽车。我们将确定EVS以及EVS的变化如何影响炎症的消退，并深入了解电动汽车在伤口愈合中的作用。在目标1中，我们将使用囊泡流用细胞术确定EV亚群，然后过继转移EVS以确定其容量激活糖尿病和免疫缺陷基因敲除小鼠的特异性免疫细胞群调解皮肤伤口闭合的模型。目标2将研究特定的RAB以确定如何这些RAB影响EV的生物发生和内容。此外，利用改装后的电动汽车 RAB环境下，我们将建立这些电动汽车对特异性免疫反应的分解动力学。总之，这些研究将确立电动汽车作为潜在疗法的相关性，并解决系统地创造专门针对皮肤修复的特定阶段进行优化的治疗性电动汽车。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tumor-Derived Extracellular Vesicles and the Immune System-Lessons From Immune-Competent Mouse-Tumor Models.

DOI：
10.3389/fimmu.2020.606859
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Droste M;Thakur BK;Eliceiri BP
通讯作者：
Eliceiri BP

Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways.

DOI：
10.1038/s41467-020-20108-0
发表时间：
2020-12-10
期刊：
Nature communications
影响因子：
16.6
作者：
Zhong C;Li P;Argade S;Liu L;Chilla' A;Liang W;Xin H;Eliceiri B;Choudhury B;Ferrara N
通讯作者：
Ferrara N

Genetic Background and Kinetics Define Wound Bed Extracellular Vesicles in a Mouse Model of Cutaneous Injury.