VASCULAR LEUKOCYTES: BASIC IMMUNOBIOLOGY AND FUNCTIONAL PLASTICITY

血管白细胞：基础免疫生物学和功能可塑性

• 批准号: 7959993
• 负责人: Jose R Conejo-Garcia
• 金额: $ 4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959993
• 关键词: Antigens; Blood Vessels; CCR6 gene; Cells; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Dendritic Cells; Development; Disease; Effectiveness; Endothelial Cells; Funding; Grant; ITGAX gene; Immune System Diseases; Immunobiology; Immunotoxins; Institution; Label; Laboratories; Leukocytes; Malignant Neoplasms; Molecular; Mus; Myelogenous; Phenotype; Physiological; Process; Recruitment Activity; Research; Research Personnel; Resources; Source; Staging; Syndrome; Testing; Therapeutic Intervention; Time; Transgenic Mice; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascularization; Work; base; beta-Defensins; cancer therapy; chemokine receptor; developmental plasticity; effective therapy; neoplastic cell; new therapeutic target; novel; tumor; tumor growth; uptake; vasculogenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent findings from our laboratory and others demonstrate that dendritic cells (DCs) have remarkable functional and developmental plasticity. Whereas the antigen uptake and presentation functions of DCs are well described, our recent work establishes that some DC precursors can also participate directly in vasculogenesis. We have defined a novel mechanism of vascularization: beta-defensins produced by tumor cells recruit myeloid leukocytes expressing the chemokine receptor CCR6 to the tumor microenvironment, where they are transformed by VEGF-A into endothelial-like cells, termed Vascular Leukocytes (VLCs). VLCs express markers - and have physiologic characteristics - of both endothelial cells and DCs. Our central hypothesis is that VLCs are a specific lineage of CD11c+ DCs that significantly contributes to vascularization during tumor formation: as such these cells may represent an important and novel therapeutic target in the treatment of cancer, and perhaps in other immunological disease syndromes. To test this hypothesis, we propose the following experimental plan: In Specific Aim 1 we will determine the origin of leukocytes with vasculogenic potential. Mice will be depleted of VLCs, and then challenged with tumors admixed with different subsets of labeled leukocytes; this will enable us to precisely define which leukocyte subset(s) are capable of contributing to vasculogenesis. Specific Aim 2 will assess the stage in tumor development at which VLCs contribute to tumor vascularization. We propose to generate a transgenic mouse with permanently "tagged" VLCs, permitting the ready identification of this subset over time, even if they lose their leukocyte phenotype during the process of endothelialization. Specific Aim 3 will evaluate the effectiveness of VLC depletion as a therapeutic intervention in cancer, focusing on the efficacy of anti-VLC immunotoxins in the abrogation of tumor growth. These endeavors will result in a better understanding of the Immunobiology and functional potential of DCs and provide a basis for more effective treatment of tumors and immunological disorders.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们实验室和其他人的最新发现表明，树突状细胞（DC）具有显着的功能性和发育可塑性。尽管很好地描述了DC的抗原摄取和表现功能，但我们最近的工作表明，某些DC前体也可以直接参与血管生成。我们已经定义了一种新型的血管形成机制：由肿瘤细胞产生的β-防御素募集髓样白细胞，将趋化因子受体CCR6表达到肿瘤微环境中，在那里vegf-a转化为内皮样细胞，被称为内皮样细胞，称为血管白细胞（VLCS）。 VLC表达内皮细胞和DC具有生理特征，并具有生理特征。我们的中心假设是，VLC是CD11C+ DC的特定谱系，在肿瘤形成过程中显着促进血管形成：因此，这些细胞可能代表了癌症治疗的重要且新颖的治疗靶标，也许是其他免疫疾病综合症。 为了检验这一假设，我们提出了以下实验计划：在特定目的1中，我们将确定具有血管生成潜力的白细胞的起源。小鼠将耗尽VLC，然后用与不同标记的白细胞子集混合的肿瘤挑战；这将使我们能够精确地定义白细胞子集有助于血管生成。特定的目标2将评估VLC有助于肿瘤血管形成的肿瘤发育阶段。我们建议以永久性的“标记” VLC生成一种转基因小鼠，即使在内皮化过程中失去了白细胞表型，也可以随时间识别该子集。具体目标3将评估VLC耗竭作为对癌症的治疗干预的有效性，重点是抗VLC免疫毒素在废除肿瘤生长中的疗效。 这些努力将更好地了解DC的免疫生物学和功能潜力，并为对肿瘤和免疫疾病的更有效治疗提供基础。