Validating Mouse Models of Prostatic Hyperplasia

SCIENTIFIC RESEARCH PROJECT: SUMMARY Benign prostatic hyperplasia (BPH) is common, resulting in significant morbidity, billions of dollars in annual medical expenses, and even greater costs to the economy in lost productivity. BPH is characterized by stromal and glandular hyperplasia, occurring focally in the transition zone of the prostate restricting urinary flow. The

underlying causes of this focal growth are still unclear. Chronic inflammation is clearly associated with BPH and some have hypothesized a causal link, but data supporting this are limited. No comprehensive description of the immune environment in the mouse prostate currently exists, likely due to the scarcity of prostatic inflammation

in background strains. Inadequate characterization of BPH models leaves them subject to scrutiny during the review process, so a direct comparison of mouse models with prostatic inflammation and hyperplasia both to one another and to human tissue is necessary to identify models appropriate to a specific research direction.

This project aims to bridge this knowledge gap by utilizing single-cell RNA-seq (scRNA-seq) to identify the similarities between murine models and human BPH with the hypothesis that specific cell states, with expression profiles that mirror those in human tissues, will be found in individual mouse models

indicating those aspects of human disease reflected in the model. The primary objective is to provide a basis to select project-appropriate BPH models through a comprehensive analysis of cellular composition and transcriptomic profiles, supplemented with measures of voiding function and histopathology. Furthermore, these

studies will provide an accessible database of cellular, pathological, and voiding function information for each model that can be used as a benchmark and expanded by the benign urologic community. The searchable database will be an invaluable resource for the BPH research community, providing guidance on murine model

selection and facilitating molecular and functional queries. Two Specific Aims will be pursued by a multidisciplinary team of three early-stage investigators (ESIs). First, we will complete a comparative cellular and functional characterization of mouse models of prostate hyperplasia. This aim will apply scRNA-seq

to individual prostate lobes of six different models of prostatic inflammation and hyperplasia, as well as immune cell profiling for T and B cell receptor sequencing in mouse models and human BPH tissues. Histopathological and voiding function evaluations will also be included. In the second aim, we will develop a reference database

and calculate the BPH-indicated functional distance between mouse and reference cellular populations. This aim will provide a bioinformatic comparison of all cells between each model as well as overlay cell types from each model to existing human scRNA-seq data to look for common cell states. Resources to make these

data available to the scientific community, as a collection in the CellxGene portal and as an RShiny application, will also be developed in this aim. We anticipate this work will lead to an improved use of current models for BPH research, provide a basis for future R01 applications by each ESI, and lead to future novel pre-clinical studies.