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

项目总结/摘要 浅表纤维化素质影响高达7-12%的美国男性人口。这些条件包括 佩罗尼氏病（PD），导致阴茎斑块和勃起期间的弯曲，和 Dupuytren病（DD），导致掌筋膜结节和手部挛缩。曾被认为是 良性的，这些条件会导致身体损害和负面影响的关系，并已被链接到 严重的心理后果包括临床抑郁症这些表面纤维化素质可以是 可遗传，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。 目前的治疗是不完全有效的，部分原因是对发病机制的理解有限， 分子和基因的贡献，这些素质。 我们小组先前的工作确定了与炎症有关的几个基因的微缺失， 易形成纤维化斑块。拟议的工作将设法了解这些候选人的作用 基因，NELL 1，CTDSPL和ZNF 277在纤维化和炎症中有助于PD和DD的体外研究 测定和动物模型。具体来说，这项基础研究调查解决了NELL 1， CTDSPL和ZNF 277调节参与纤维化和炎症的信号通路， 在基因剂量或功能上可使异常胶原沉积和纤维化斑块形成倾向。的 拟议的工作将确定NELL 1、CTDSPL和ZNF 277表达和功能改变的影响 对来源于PD和/或DD患者和遗传改变小鼠的成纤维细胞中的TGF-β途径， 以及体外对胶原沉积和纤维化的影响。我们还将调查缺乏的影响 这些基因对系统性和阴茎纤维化的影响， 在这些基因中建立遗传缺陷的因果关系。 我们项目的第二个目标是利用犹他州人口数据库（UTB）来识别PD的家族性病例 和DD，并确定这些患者的相关共病状况。探索性分析，以确定 家族性PD和DD病例中的因果性遗传改变，重点关注TGF-β通路相关基因， 也将被执行。 从这项工作中获得的数据将提供一个详细的了解如何NELL 1，CTDSPL，和ZNF 277 在分子水平上影响异常纤维化的形成，也将导致对 与PD和DD相关的遗传影响疾病谱。这些数据将 为改善患者诊断、风险分层和靶向治疗提供基础。

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.