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

佩罗尼氏病和掌腱膜挛缩症易发生纤维化和炎症的遗传变异的验证和鉴定

• 批准号: 10367284
• 负责人: Alexander Wojciech Pastuszak
• 金额: $ 61.72万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367284
• 关键词: Address; Affect; Animal Model; Basic Science; Benign; Biological Assay; CRISPR/Cas technology; Candidate Disease Gene; Cells; Coitus; Collagen; Contracture; DNA Sequence Alteration; Data; Databases; Defect; Deformity; Deposition; Development; Diagnosis; Disease; Epidermal Growth Factor; Etiology; Extended Family; Family member; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gene Dosage; Gene Expression; Genealogy; Genes; Genetic; Genetic Diseases; Genetic Polymorphism; Genetic Screening; Genetic Transcription; Goals; Hand; Health; Heritability; High Prevalence; Human; Hydroxyproline; Immunohistochemistry; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Link; Major Depressive Disorder; Malignant Neoplasms; Medical Records; Molecular; Molecular Genetics; Mus; Mutation; Neurophysiology - biologic function; Nodule; Organ; Other Genetics; Pathogenesis; Pathogenicity; Pathway interactions; Patient risk; Patients; Peyronie Disease; Phosphoric Monoester Hydrolases; Population; Population Database; Predisposition; Proteins; Role; Science; Sexual Dysfunction; Signal Pathway; Testing; Transforming Growth Factor beta; Trichrome stain method; Tunica Albuginea; United States; Utah; Validation; Variant; Work; Zinc Fingers; animal data; clinical diagnosis; clinical risk; comorbidity; differential expression; effective therapy; erection; gene function; genetic pedigree; genetic variant; genome sequencing; high risk; human data; improved; in vitro Assay; inflammatory marker; interest; male; men; microdeletion; molecular targeted therapies; mouse model; negative affect; patient stratification; penis; psychologic; recruit; relating to nervous system; risk stratification; targeted treatment; transcriptome sequencing; translational model; translational study; whole genome

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.

项目概要/摘要 高达 7-12% 的美国男性人口患有浅表纤维化素质。这些条件包括 佩罗尼氏病 (PD)，会导致阴茎出现斑块并导致勃起时弯曲，以及 掌腱膜挛缩症 (DD)，导致掌筋膜结节和手部挛缩。虽然考虑 这些情况虽然是良性的，但会导致身体损伤并对人际关系产生负面影响，并且与 显着的心理影响，包括临床抑郁症。这些浅表纤维化素质可以是 具有遗传性，15-22% 的患者共存，并且可能与其他遗传疾病（包括恶性肿瘤）有关。 目前的治疗方法并不完全有效，部分原因是对发病机制的了解有限，并且 这些素质的分子和遗传贡献。 我们小组之前的工作发现了与炎症有关的几个基因的微缺失，这可能是 容易形成纤维化斑块。拟议的工作将寻求了解这些候选人的角色 体外研究基因 NELL1、CTDSPL 和 ZNF277 在导致 PD 和 DD 的纤维化和炎症中的作用 测定和动物模型。具体来说，这项基础研究调查提出了 NELL1 的假设， CTDSPL 和 ZNF277 调节参与纤维化和炎症的信号通路，并且这种改变 基因剂量或功能的变化可能导致异常胶原沉积和纤维化斑块形成。这 拟议的工作将确定 NELL1、CTDSPL 和 ZNF277 表达和功能改变的影响 对来自 PD 和/或 DD 患者以及基因改造小鼠的成纤维细胞中的 TGF-β 通路的影响， 以及对体外胶原沉积和纤维化的影响。我们还将调查缺陷的影响 使用基因改造的小鼠模型来更明确地研究这些基因对系统性纤维化和阴茎纤维化的影响 确定这些基因的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 (UPDB) 来识别 PD 家族病例 和 DD 并确定这些患者的相关合并症。探索性分析以确定 家族性 PD 和 DD 病例的因果遗传改变，重点关注参与 TGF-β 途径的基因， 也将进行。 从这项工作中获得的数据将帮助您详细了解 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 PD 和 DD 相关的一系列受遗传影响的疾病。这些数据一起将 为改善患者诊断、风险分层和针对性治疗奠定基础。