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.