Initiation and Regulation of Chronic Autoimmune Prostate Inflammation

慢性自身免疫性前列腺炎症的引发和调节

• 批准号: 8481541
• 负责人: Timothy L. Ratliff
• 金额: $ 31.84万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481541
• 关键词: Animal Model; Atrophic; Autoimmune Process; Autoimmunity; Basic Amino Acid Transport Systems; Benign Prostatic Hypertrophy; Binding; Cell physiology; Cells; Chronic; Chronic Prostatitis; Clinical; Code; Data; Disease; Epidemiology; Epithelial Cells; Foundations; Funding; Genes; Glutathione S-Transferase; Histopathology; Hyperplasia; IL8 gene; Immune response; Inflammation; Inflammatory; Inflammatory Infiltrate; Interferons; Interleukin-6; Intervention; Link; Liver; MAPK14 gene; Malignant neoplasm of prostate; Membrane; Modeling; Myelogenous; Oncogenes; Ovalbumin; Pathway interactions; Patients; Pelvic Pain; Peptides; Process; Production; Prostate; Prostatic; Prostatic Diseases; Proteins; Regulation; Regulatory Pathway; Ribonucleases; Role; Signal Pathway; Site; Specimen; Spleen; Staging; Suppressor-Effector T-Lymphocytes; Symptoms; T cell regulation; T cell response; T-Lymphocyte; TNF gene; Tissues; Transgenic Mice; Tumor Necrosis Factor-alpha; adenoma; base; cell type; chronic pelvic pain; cytokine; human disease; inhibitor/antagonist; intraepithelial; macrophage scavenger receptors; mouse model; novel; novel strategies; peripheral blood; precursor cell; response

DESCRIPTION (provided by applicant): Chronic non-bacterial inflammation of the prostate is associated with multiple prostate diseases including chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS), benign prostatic hyperplasia (BPH), and prostate cancer. The multiplicity of associations between prostate diseases and inflammation provide a strong rationale for better understanding the origin and regulation of prostate inflammation. While the cause of prostate inflammation has not been conclusively determined, T cell specific autoimmunity has been linked to prostate inflammatory processes both clinically and in animal models. Thus, studies to define autoimmune prostate inflammation and its regulation are needed to provide a better understanding of the inflammatory process and to identify potential points of intervention to reduce or eliminate inflammation. We developed a novel transgenic mouse model expressing membrane bound ovalbumin exclusively on prostate epithelial cells to investigate prostate inflammatory processes and its regulation. Studies during the past funding period showed an important role for myeloid-derived suppressor cells (MDSC) in the regulation of prostate inflammation. MDSC were observed as the dominant cell type in the inflammatory infiltrate during the first 10- 14 days of the response. Inhibition of MDSC regulation of T cells enhanced inflammation. Notably, functional MDSC were observed to be localized to the inflamed prostate, whereas phenotypically identical cells in the spleen and liver were classified as precursor cells, setting the stage for differential identification of pathways linked to MDSC function. Preliminary data shown herein show that a novel peptide inhibitor of inflammation and MDSC function was identified that links MDSC function and inflammatory cytokine levels in prostate inflammation to the p38 signaling pathway. Moreover, the cationic amino acid transporter that functions to deliver L-Arg to MDSC was identified. Finally, data were generated demonstrating an elevation of MDSC in the peripheral blood of patients with CP-CPPS compared to controls, suggesting a role in human disease. These data provide a foundation for the hypothesis that cytokine production and T cell regulation by MDSC are central to prostate inflammation and its regulation. Further, localization of MDSC function to the site of inflammation provides a basis for differentially identifying additional pathways linked to MDSC function. Studies outlined in this application propose to further define the regulatory pathways of MDSC with the intent of developing novel approaches to controlling prostate inflammation both in the POET-3 model and clinical specimens from CP-CPPS patients. To this end the following specific aims are proposed. Specific Aim 1. Define myeloid-derived suppressor cell pathways/molecules in the POET-3 model and clinical setting of CP-CPPS central to controlling prostate inflammation. Hypothesis: Understanding the cellular molecules/pathways controlling MDSC regulation of T cell responses and cytokine production will provide avenues for dissecting functional implications of MDSC in modulating prostate inflammation. Specific Aim 2. Define the impact of myeloid-derived suppressor cell regulation on prostate inflammation and prostate histopathology. Hypothesis: Myeloid-derived suppressor cells, although present early and transiently, are central to the regulation of prostate inflammation through inhibition of T cell responses and control of cytokine production at the inflammatory site.

描述（申请人提供）：前列腺慢性非细菌性炎症与多种前列腺疾病相关，包括慢性前列腺炎-慢性盆腔疼痛综合征（CP-CPPS）、良性前列腺增生（BPH）和前列腺癌。前列腺疾病和炎症之间的多重关联为更好地了解前列腺炎症的起源和调节提供了强有力的理由。虽然前列腺炎症的病因尚未最终确定，但在临床和动物模型中，T 细胞特异性自身免疫与前列腺炎症过程有关。因此，需要进行研究来定义自身免疫性前列腺炎症及其调节，以更好地了解炎症过程并确定减少或消除炎症的潜在干预点。我们开发了一种新型转基因小鼠模型，仅在前列腺上皮细胞上表达膜结合卵清蛋白，以研究前列腺炎症过程及其调节。过去资助期间的研究表明，骨髓源性抑制细胞（MDSC）在前列腺炎症的调节中发挥着重要作用。在反应的前 10-14 天期间，观察到 MDSC 是炎症浸润中的主要细胞类型。抑制 T 细胞的 MDSC 调节会增强炎症。值得注意的是，功能性 MDSC 被观察到位于发炎的前列腺，而脾脏和肝脏中表型相同的细胞被分类为前体细胞，为与 MDSC 功能相关的通路的差异识别奠定了基础。本文显示的初步数据表明，鉴定出一种新型炎症和 MDSC 功能肽抑制剂，它将前列腺炎症中的 MDSC 功能和炎症细胞因子水平与 p38 信号通路联系起来。此外，还鉴定出了能够将 L-Arg 递送至 MDSC 的阳离子氨基酸转运蛋白。最后，生成的数据表明，与对照组相比，CP-CPPS 患者外周血中 MDSC 升高，表明其在人类疾病中发挥作用。这些数据为以下假设提供了基础：MDSC 产生的细胞因子和 T 细胞调节是前列腺炎症及其调节的核心。此外，MDSC 功能定位于炎症部位提供了基础 差异化识别与 MDSC 功能相关的其他途径。本申请中概述的研究建议进一步定义 MDSC 的调控途径，旨在开发新方法来控制 POET-3 模型和 CP-CPPS 患者临床标本中的前列腺炎症。为此，提出以下具体目标。具体目标 1. 定义 POET-3 模型中的骨髓源性抑制细胞途径/分子以及控制前列腺炎症的 CP-CPPS 临床环境。假设：了解控制 MDSC 对 T 细胞反应和细胞因子产生的调节的细胞分子/途径将为剖析 MDSC 在调节前列腺炎症中的功能意义提供途径。具体目标 2. 定义骨髓源性抑制细胞调节对前列腺炎症和前列腺组织病理学的影响。假设：骨髓源性抑制细胞虽然存在较早且短暂，但通过抑制 T 细胞反应和控制炎症部位细胞因子的产生，对于前列腺炎症的调节至关重要。