Localized Vulvodynia Pathogenesis: Fibroblast, Yeast, and Melanocortin

局限性外阴痛发病机制：成纤维细胞、酵母菌和黑皮质素

• 批准号: 8334763
• 负责人: DAVID Charles FOSTER
• 金额: $ 31.31万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334763
• 关键词: Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biological Assay; Biology; Cell Wall; Cells; Chronic; Clinical; Colorimetry; Development; Dinoprostone; Dyspareunia; Epidemiology; Exhibits; Exposure to; Fibroblasts; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genital system; Goals; Human Genetics; IL8 gene; Immunohistochemistry; Immunologics; In Situ; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Irritants; Measures; Mediating; Mediator of activation protein; Melanocortin 1 Receptor; Molecular; Operative Surgical Procedures; Outcomes Research; Pain; Pain Map; Painless; Pathogenesis; Patients; Pattern; Play; Premenopause; Prevention; Pro-Opiomelanocortin; Production; Prostaglandins; Publishing; Regulation; Reporting; Research; Research Proposals; Risk; Role; Sampling; Series; Signal Transduction; Single Nucleotide Polymorphism; Site; Skin; Specimen; Stimulus; Surface; TLR2 gene; TLR4 gene; Testing; Therapeutic; Therapeutic Studies; Tissues; Toll-like receptors; Vestibule; Vulva; Vulvodynia; Woman; Yeasts; base; chronic pain; cytokine; disease classification; disorder prevention; experience; inflammatory pain; inhibitor/antagonist; loss of function; lysylproline; multidisciplinary; response; skin color

DESCRIPTION (provided by applicant): This R01 application responds to PAR-10-190: "Vulvodynia - Systematic Epidemiologic, Etiologic or Therapeutic Studies." Our long-term goal is to develop an understanding of the vulvodynia pain mechanism leading to a mechanism-based disease classification and ultimately to a mechanism-based therapy. Our research team has reported a mechanistic connection between yeast products, regional fibroblast activation, pro-opiomelanocortins, and localized provoked vulvodynia (LPV). Fibroblasts are now recognized as more than structural cells as they not only respond to signals but can prodigiously produce many different biologic mediators, including those that promote pain. Fibroblasts also exhibit considerable regional specialization. We discovered that fibroblasts from the vulvar vestibule produce markedly elevated levels of pro-inflammatory, pro-pain mediators following activation with yeast cell wall products. In particular, heightened pro-inflammatory mediator responses are generated by fibroblasts from the vulvar vestibule of LPV-afflicted women. This may be related to single nucleotide polymorphisms (SNP) in the melanocortin-1 receptor (MC1R) that enhance inflammatory mediator production. We propose that the vulvar vestibule of all women possesses a unique inflammatory/pain-inducing responsiveness and that vulvodynia pain reflects an extreme but natural inflammatory phenomenon. We hypothesize that vulvodynia arises 1) in a region of the genital tract predisposed to inflammation, 2) in the presence of specific irritants such as yeast, that are 3) exacerbated by genetic predisposition. To significantly advance and impact the field, we have assembled a multidisciplinary team, experienced in LPV, fibroblast biology, and inflammation to achieve the following three aims. Specific Aim 1: To determine whether pro-inflammatory fibroblasts segregate to painful areas of the vulva. Using lower genital tract pain mapping, we will discover whether pro-inflammatory fibroblasts localize to painful anatomic regions in situ. Fibroblast strains will be developed from painful and non-painful areas of the vulva and their biosynthetic capabilities for pro-inflammatory and other mediators determined after exposure to key fibroblast activating cytokines. Specific Aim 2: To determine whether yeast or yeast products activate fibroblasts via Toll-like receptors (TLR) and whether specific MC1R SNPs modify that response. We will determine whether the LPV-afflicted patients carry a different pattern of yeast species and yeast load, and whether yeast cell wall products initiate, through toll-like receptors, a pro-inflammatory, pain-inducing response from fibroblasts derived from painful regions. Specific Aim 3: To determine whether pro-opiomelanocortin "loss-of-function" promotes vulvodynia. We will investigate whether "loss-of-function" melanocortin-1 receptor SNPs enhance site-specific fibroblast activation, and can be identified with a simple clinical measure, skin colorimetry. We will assess an anti-inflammatory melanocortin derivative with therapeutic potential for vulvodynia and investigate the underlying molecular mechanism(s). PUBLIC HEALTH RELEVANCE: Our research goal is to identify a target cell residing in painful regions of the vulva that responds with a heightened pro-inflammatory, pain-generating response to common environmental stimuli. Through this goal we wish to develop an understanding of the vulvodynia pain mechanism, leading to a mechanism-based classification of disease, and ultimately leading to mechanism-based therapeutics and prevention.

描述（由申请人提供）：此R01应用程序对10-190 pars响应：“外阴痛 - 系统流行病学，病因学或治疗研究。”我们的长期目标是对外阴痛的疼痛机制有一种理解，导致基于机制的疾病分类，并最终进行基于机制的治疗。我们的研究团队报告了酵母产品，区域成纤维细胞激活，促蛋白酶皮质素和局部挑衅的外阴痛（LPV）之间的机械联系。现在，成纤维细胞被认为是结构性细胞，因为它们不仅对信号有反应，而且可以大量产生许多不同的生物介质，包括促进疼痛的生物介质。成纤维细胞也表现出相当大的区域专业化。我们发现，在用酵母细胞壁产物激活后，来自外阴前庭的成纤维细胞产生的促炎性疾病介质的水平明显升高。特别是，促炎性介质反应的增强是由lpv育妇女外阴前庭的成纤维细胞产生的。这可能与黑色皮质素-1受体（MC1R）中的单核苷酸多态性（SNP）有关，从而增强炎症介质产生。我们建议所有女性的外阴前庭都具有独特的炎症/疼痛的反应性，而外阴痛的疼痛反映了一种极端但自然的炎症现象。我们假设外阴痛是1）在易于炎症的生殖道的区域中产生的，2）在存在特定刺激物（例如酵母）的存在下，3）因遗传倾向而加剧。为了显着进步和影响该领域，我们组建了一个多学科团队，该团队在LPV，成纤维细胞生物学和炎症方面经历了以下三个目标。具体目的1：确定促炎性成纤维细胞是否隔离到外阴的痛苦区域。使用较低的生殖道疼痛映射，我们将发现促炎性成纤维细胞是否本地化为疼痛的解剖区域。成纤维细胞菌株将从外阴的痛苦和非抚摸区域及其生物合成能力开发，用于暴露于关键成纤维细胞激活细胞因子后确定的促炎和其他介质。特定目标2：确定酵母菌或酵母产品是否通过Toll样受体（TLR）激活成纤维细胞，以及特定的MC1R SNP是否会改变该反应。我们将确定由LPV伴有的患者是否具有不同的酵母菌和酵母负荷的模式，以及酵母细胞壁产品是否通过Toll样受体，促炎的促疼痛的疼痛反应启动，从疼痛区域衍生出的成纤维细胞。特定目的3：确定促蛋白聚糖素的“功能丧失”是否促进外阴痛。我们将调查“功能丧失”黑素皮质素-1受体SNP是否可以增强位点特异性成纤维细胞激活，并可以通过简单的临床测量（即肤色比色法）来识别。我们将评估具有外阴痛的治疗潜力的抗炎黑素皮质衍生物，并研究潜在的分子机制。 公共卫生相关性：我们的研究目标是确定居住在外阴疼痛地区的靶细胞，其反应增强，对常见环境刺激的促痛性，疼痛的反应。通过这个目标，我们希望对外阴痛的疼痛机制有一种理解，从而导致基于机制的疾病分类，并最终导致基于机制的疗法和预防。