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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：
7935051
负责人：
DAVID R ROWLEY
金额：
$ 6.94万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7935051
关键词：
Acinus organ component Address Adoptive Transfer Age Attenuated Benign Prostatic Hypertrophy Biological Models Biology Bone Marrow Transplantation CD34 gene Cell Proliferation Cells Characteristics Chemotaxis Chimera organism Chronic Clinical Data Clinical Trials Collagen Data Deposition Development Disease Drug usage Engineering Epithelial Epithelial Cells Epithelium Etiology Exhibits Extracellular Matrix Fibroblasts Future Gene Expression Gene Expression Profiling Genes Genetic Recombination Goals Growth Factor Homologous Gene Human Human Biology Hyperplasia IL8 gene IL8RB gene Individual Inflammation Inflammatory Interleukin-8 Interleukin-8B Receptor Knockout Mice Label Lasers Lead Marrow Mediator of activation protein Microscopy Molecular Profiling Mus Myeloid Progenitor Cells Myofibroblast Pathway interactions Pharmaceutical Preparations Phenotype Production Prostate Prostatic Prostatic hypertrophy Receptor Signaling Recruitment Activity Regulatory Pathway Reporting Role Signal Transduction Site Stem cells Stromal Cells Stromal Hyperplasia Tenascin Therapeutic Tissues Transgenic Mice Transgenic Organisms Work Wound Healing Xenograft Model angiogenesis attenuation cDNA Arrays cell stroma cell type chemokine design keratinocyte novel novel therapeutic intervention novel therapeutics overexpression pre-clinical progenitor response therapeutic target tissue fixing treatment strategy

项目摘要

Benign prostatic hyperplasia (BPH) is a common age-associated disorder 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 of tenascin. IL-8 is a potent chemokine that induces chemotaxis of many cell types stimulates reactive stroma / wound repair mechanisms. We have generated a transgenic mouse expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and stromal phenotype with elevated tenascin-C and pro-collagen I expression. Our preliminary data suggests that reactive stroma is recruited from both local tissue-fixed and circulating marrow-derived CD34+ progenitor fibrocyte 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. Together, these studies will pinpoint the role of IL-8 in recruiting reactive stroma and inducing the hyerplastic phenotype. The purpose of this project is to provide proof of concept and key data, from which to build a strategic approach to support clinical trials. The long-range goal of this work is to develop a novel therapeutic strategy that targets components of the IL-8 / CXCR2 regulatory pathway for the treatment of BPH.

良性前列腺增生（BPH）是一种常见的年龄相关疾病，以上皮和间质为典型