Validation and Identification of Genetic Variants in Peyronie's and Dupuytren's Disease that Predispose to Fibrosis and Inflammation

项目摘要/摘要 浅表性纤维性疾病影响高达7-12%的美国男性人口。这些条件包括 Peyronie病(PD)，在勃起过程中导致阴茎斑块和由此产生的曲度，以及 Dupuytren病(DD)，导致手掌筋膜结节和手部痉挛。当考虑到 良性的，这些疾病会导致身体损伤，并对人际关系产生负面影响，并与 严重的心理影响，包括临床抑郁症。这些表面的纤维化疾病可能是 可遗传的，在15%-22%的患者中共存，并可能与其他遗传疾病有关，包括恶性肿瘤。 目前的治疗方法并不完全有效，部分原因是对该病的发病机制了解有限。 分子和遗传因素对这些疾病的影响。 我们小组之前的工作发现了几个与炎症有关的基因的微缺失，这些基因可能 易形成纤维性斑块。拟议的工作将寻求了解这些候选人的角色 肝纤维化和炎症相关基因NELL1、CTDSPL和ZNF277促进PD和DD的体外研究 化验和动物模型。具体地说，这项基础研究调查解决了NELL1， CTDSPL和ZNF277调节参与纤维化和炎症的信号通路，以及这种变化 在基因剂量或功能方面，易导致胶原异常沉积和纤维化斑块形成。这个 拟议的工作将定义NELL1、CTDSPL和ZNF277的表达和功能变化的影响 关于PD和/或DD患者和转基因小鼠成纤维细胞转化生长因子-β途径的研究 以及对胶原沉积和体外纤维化的影响。我们还将调查缺陷的影响 利用转基因小鼠模型更明确地研究这些基因对系统性和阴茎纤维化的影响 在这些基因的遗传缺陷的背景下建立因果关系。 我们项目的第二个目标将利用犹他州人口数据库(UPDB)来识别帕金森病家族病例 和DD，并确定这些患者的相关合并情况。探索性分析以确定 家族性PD和DD患者的原因基因改变，重点是转化生长因子-β途径涉及的基因， 也将上演。 从这项工作中获得的数据将提供对NELL1、CTDSPL和ZNF277如何 在分子水平上影响异常纤维化的形成，也将导致对 与帕金森病和痴呆症相关的遗传影响疾病的谱系。这些数据加在一起将 为改善患者诊断、风险分层和有针对性的治疗提供基础。

PROJECT SUMMARY / ABSTRACT Superficial fibrotic diatheses affect up to 7-12% of the United States male population. These conditions include Peyronie’s Disease (PD), which results in penile plaques and resulting curvature during erection, and Dupuytren’s Disease (DD), resulting in nodules of the palmar fasciae and hand contracture. While considered benign, these conditions cause physical impairment and negatively affect relationships, and have been linked to significant psychological ramifications, including clinical depression. These superficial fibrotic diatheses can be heritable, co-existing in 15-22% of patients, and may be linked to other genetic conditions, including malignancy. Current treatments are incompletely effective, in part due to a limited understanding of the pathogenesis of, and molecular and genetic contributions to, these diatheses. Previous work by our group identified microdeletions in several genes implicated in inflammation that may predispose to fibrotic plaque formation. The proposed work will seek to understand the roles of these candidate genes, NELL1, CTDSPL, and ZNF277 in fibrosis and inflammation contributing to PD and DD using in vitro assays and animal models. Specifically, this basic research investigation addresses the hypothesis that NELL1, CTDSPL, and ZNF277 modulate signaling pathways involved in fibrosis and inflammation, and that alterations in gene dosage or function can predispose to aberrant collagen deposition and fibrotic plaque formation. The proposed work will define the impact of alterations in expression and function of NELL1, CTDSPL, and ZNF277 on the TGF-β pathway in fibroblasts derived from patients with PD and/or DD and from genetically altered mice, as well as the impact on collagen deposition and fibrosis in vitro. We will also investigate the impact of deficiency of these genes on systemic and penile fibrosis using genetically altered mouse models to more definitively establish causality in the setting of genetic defects in these genes. The second aim of our project will utilize the Utah Population Database (UPDB) to identify familial cases of PD and DD and to determine associated comorbid conditions in these patients. An exploratory analysis to identify causal genetic alterations in familial PD and DD cases, with a focus on genes involved in the TGF-β pathway, will also be performed. The data obtained from this work will provide a detailed understanding of how NELL1, CTDSPL, and ZNF277 influence the formation of aberrant fibrosis on a molecular level and will also result in an understanding of the spectrum of genetically influenced conditions that are associated with PD and DD. Together, these data will provide the groundwork for improving patient diagnosis, risk stratification, and targeted treatment.