Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

Interleukin-8 在良性前列腺增生中的诱导生物学作用

基本信息

批准号：
8322849
负责人：
DAVID R ROWLEY
金额：
$ 32.15万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322849
关键词：
Acinus organ component Address Adoptive Transfer Age Attenuated Benign Prostatic Hypertrophy Biological Models Biology Bone Marrow Transplantation CD14 gene Caliber Cell Proliferation Cells Characteristics Chemotaxis Chronic Collagen Data Deposition Development Disease Drug usage Epithelial Epithelium Etiology Exhibits Extracellular Matrix Fibroblasts Future Gene Expression Gene Expression Profiling Genes Goals Growth Factor Homologous Gene Human Hyperplasia IL8 gene IL8RB gene Inflammation Inflammatory Interleukin-8 Interleukin-8B Receptor Lead Marrow Mediator of activation protein Modeling Mus Myeloid Progenitor Cells Myofibroblast Pathway interactions Pattern Phenotype Production Prostate Prostatic Prostatic hypertrophy Receptor Signaling Recruitment Activity Reporting Role Signal Transduction Site Stem cells Stromal Cells Stromal Change Stromal Hyperplasia Tenascin Therapeutic Tissues Transgenic Mice Transgenic Organisms Work Wound Healing Xenograft Model Xenograft procedure angiogenesis attenuation cell stroma cell type chemokine keratinocyte mouse model novel novel therapeutic intervention overexpression progenitor public health relevance research study response therapeutic target treatment strategy

Acinus organ component Address Adoptive Transfer Age Attenuated Benign Prostatic Hypertrophy Biological Models Biology Bone Marrow Transplantation CD14 gene Caliber Cell Proliferation Cells Characteristics Chemotaxis Chronic Collagen Data Deposition Development Disease Drug usage Epithelial Epithelium Etiology Exhibits Extracellular Matrix Fibroblasts Future Gene Expression Gene Expression Profiling Genes Goals Growth Factor Homologous Gene Human Hyperplasia IL8 gene IL8RB gene Inflammation Inflammatory Interleukin-8 Interleukin-8B Receptor Lead Marrow Mediator of activation protein Modeling Mus Myeloid Progenitor Cells Myofibroblast Pathway interactions Pattern Phenotype Production Prostate Prostatic Prostatic hypertrophy Receptor Signaling Recruitment Activity Reporting Role Signal Transduction Site Stem cells Stromal Cells Stromal Change Stromal Hyperplasia Tenascin Therapeutic Tissues Transgenic Mice Transgenic Organisms Work Wound Healing Xenograft Model Xenograft procedure angiogenesis attenuation cell stroma cell type chemokine keratinocyte mouse model novel novel therapeutic intervention overexpression progenitor public health relevance research study response therapeutic target treatment strategy

展开

项目摘要

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression patterns of tenascin. IL-8 is a potent chemokine that induces chemotaxis of marrow-derived cells and stimulates reactive stroma / wound repair mechanisms. We have generated a human xenograft model that overexpresses IL-8 and transgenic mouse lines expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and reactive stroma phenotype induced by IL-8(KC) with elevated tenascin-C and pro- collagen I. Our preliminary data suggests that reactive stroma may be recruited from circulating marrow- derived progenitor fibrocyte (CD14+) cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. The purpose of this project is to determine basic mechanisms of IL-8 action in recruiting reactive stroma and establish proof-of-concept that reactive stroma progenitor cells and subsequent reactive stroma can be targeted to uncouple key pathways in order to attenuate the hyperplastic phenotype. PUBLIC HEALTH RELEVANCE: This objective of this study is to determine how interleukin-8 (IL-8) regulates the biology of benign prostatic hyperplasia. This project will provide data on key mechanisms and pathways using several model systems. These mechanisms and pathways may evolve as therapeutic targets.

描述（由申请人提供）：良性前列腺增生（BPH）的特征是上皮和基质增生和前列腺的进行性增大。 BPH与慢性炎症有关，但是特定机制尚不清楚。我们报道了增生BPH上皮过表达白介素-8（IL-8），并且该上皮与替纳斯蛋白的表达模式改变的肌成纤维细胞反应性基质表型显着相关。 IL-8是一种有效的趋化因子，可诱导骨髓衍生细胞的趋化性并刺激反应性基质 /伤口修复机制。我们已经产生了一个人类异种移植模型，该模型过表达了表达KC的IL-8和转基因小鼠系（IL-8的鼠同源物），并观察到由IL-8（KC）诱导的增生性上皮上皮和反应性基质表型，其呈现较高的tenascin-c和proliminal colloic colluitional colluitival selroriatiential colluitival selroriatient croperiential colluitival syrow s crounder，均可促进。纤维细胞（CD14+）细胞。我们的假设是，升高IL-8功能激活和/或募集腺体BPH焦点的反应性基质祖细胞，并且这种增生的反应性基质进一步驱动BPH腺体和基质增生。为了解决这一假设，提出了三个具体目标：1。表征IL-8（KC） / CXCR2信号传导和Tenascin-C作为下游效应子在诱导前列腺增生中的作用。 2。确定IL-8 / CXCR2受体信号传导在反应性基质祖细胞募集中的作用。 3。使用药物诱导的基因表达在反应性基质细胞中靶向IL-8（KC） / CXCR2信号传导，以取消信号传导，从而减弱BPH中反应性基质和上皮增生的起源。该项目的目的是确定IL-8作用在募集反应性基质中的基本机制，并确定概念概念证明反应性基质祖细胞和随后的反应性基质可以靶向取消关键途径，以减轻增生表型。公共卫生相关性：这项研究的目的是确定白介素8（IL-8）如何调节良性前列腺增生的生物学。该项目将使用多个模型系统提供有关关键机制和途径的数据。这些机制和途径可能会作为治疗靶标发展。