Effects of Epigenetic Regulation in Chronic Pelvic Pain Syndrome

表观遗传调控对慢性盆腔疼痛综合征的影响

• 批准号: 10448336
• 负责人: PRAVEEN THUMBIKAT
• 金额: $ 24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448336
• 关键词: Affect; Age; Animal Model; Anogenital region; Autoimmune; Automobile Driving; Azacitidine; Bacterial Infections; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Prostatitis; Code; Complex; CpG Islands; DNA Methylation; Data; Defect; Detection; Development; Diagnosis; Dysuria; Epigenetic Process; Etiology; Event; FOXP3 gene; Genes; Human; Human Activities; Hypermethylation; IL7 gene; ITGAL gene; Immune; Immune response; Individual; Infectious Agent; Inflammation; Inflammatory; Interleukin-10; Lead; Leukocytes; Link; Lipopolysaccharides; Massage; Mediating; Medical; Methodology; Methylation; Modeling; Mus; Nature; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Prevention; Prostate; Prostatic; Regulation; Regulatory T-Lymphocyte; Role; Site; Symptoms; Syndrome; T-Lymphocyte; Testing; Testis; Therapeutic; Transgenic Organisms; United States; Urine; autoreactive T cell; chronic pain; chronic pelvic pain; cytokine; early life stress; effective therapy; epigenetic regulation; illness length; immune activation; immunoregulation; male; men; mouse model; novel therapeutics; patient subsets; penis; peripheral blood; prevent; promoter; prostatitis; protein expression; trafficking; treatment strategy

PROJECT SUMMARY CPPS is a condition that is estimated to affect up to 15% of the male population with most diagnoses between the ages of 35-45. Designated by the presence of pain in the absence of bacterial infection for more than three months, it has unknown, probably complex etiology, which thus far have hampered efforts to determine effective treatment strategies . The heterogeneous nature of the symptoms and the length of the disease course prior to detection, presentation or diagnosis only further exacerbate these issues. This proposal seeks to identify defects in immune activation or regulation that may affect a subset of patients with CP/CPPS. This subset appears to have a reduced ability to mount a regulatory immune response, while simultaneously eliciting an exaggerated activated immune response. The defects that we demonstrate appear to be linked to altered methylation of genes involved in both immune regulation and immune activation. The aims of this proposal will provide definitive evidence of a role for epigenetic changes in immune cells in patients with CP/CPPS. This is conceptually a major advance – as a variety of factors including early life stress events, prostate infectious agents, environmental variables, all could contribute to epigenetic change and may therefore explain both the anecdotal etiologies described in this syndrome as well as the difficulty in pinpointing a precise etiological mechanism. Specifically, our data leads us to hypothesize that epigenetic alterations in regulatory and proinflammatory immune pathways underpin the development of chronic pelvic pain in CPPS. In this application, we propose to validate our preliminary findings in a larger set of CP/CPPS patients and controls as well as utilize murine models of prostatitis to understand the mechanism driving altered IL-10 and IL-7/LFA-1 mediated immune responses both at systemic and prostate levels. If epigenetic defects and functional deficits can be demonstrated, diagnosis and treatment methodologies could be better targeted at correction of these chronic deficits rather than at etiological agents/pathways that are in the past.

项目摘要 CPPS是一种估计影响高达15%的男性人群的疾病，大多数诊断年龄在 35-45.指定的疼痛的存在下，在没有细菌感染超过三个月，它有 病因未知，可能很复杂，迄今为止，这阻碍了确定有效治疗策略的努力。 症状的异质性和疾病过程的长度之前，检测，表现或 诊断只会进一步加剧这些问题。这一建议旨在确定免疫激活或调节的缺陷 这可能会影响CP/CPPS患者的子集。这个子集似乎有一个降低的能力，安装一个监管 免疫反应，同时引发夸大的激活免疫反应。我们的缺点 表明似乎与参与免疫调节和免疫调节的基因的甲基化改变有关。 activation.这项提案的目的将提供明确的证据，证明免疫细胞的表观遗传变化在免疫系统中的作用。 CP/CPPS患者这在概念上是一个重大的进步--因为包括早期生活压力事件在内的各种因素， 前列腺感染因子，环境变量，都可能有助于表观遗传变化，因此可以解释 在这种综合征中描述的轶事病因以及在确定精确病因方面的困难 机制具体地说，我们的数据使我们假设，调节和促炎症反应的表观遗传改变， 免疫途径支持慢性盆腔疼痛的发展。在本申请中，我们建议验证 我们在CP/CPPS患者和对照组中的初步发现，以及利用小鼠前列腺炎模型， 了解在全身和全身免疫中驱动改变的IL-10和IL-7/LFA-1介导的免疫应答的机制， 前列腺水平如果表观遗传缺陷和功能缺陷可以证明，诊断和治疗方法 可以更好地针对这些慢性缺陷的纠正，而不是针对 过去