Date of Award

Summer 8-31-2025

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Jill Macoska

Abstract

ABSTRACT

IDENTIFYING NOVEL FIBROTIC MECHANISMS UNDERLYING TREATMENT-RESISTANT LOWER URINARY TRACT DYSFUNCTION

August 2025

Quentin D’Arcy, B.S., University of Massachusetts Amherst

Ph.D., University of Massachusetts Boston

Directed by Dr. Jill Macoska

Lower urinary tract dysfunction (LUTD) is a common, age-related disease that affects millions of men over the age of 50. Current treatment for this and other related prostate diseases concentrate on decreasing benign prostate growth and relaxing smooth muscle contractions to alleviate urinary voiding symptoms. However, up to 45% of patients with LUTD are treatment-resistant and require surgical intervention to resolve prostate issues. By focusing on the contribution of inflammation-derived prostate fibrosis my project seeks to utilize a multi-part approach to close the gap between treatment receptive and treatment resistant LUTD. The first approach concerns the IL-4/IL-13 signaling pathway, a relatively unexplored fibrotic pathway which may be the key to dealing with inflammation-derived prostate fibrosis. The second approach looks at prostate supplements, which are notoriously understudied despite being taken by millions of men suffering from LUTD and BPH. The third approach explores the contribution of regulatory RNAs to pro-fibrotic mechanisms in prostate fibroblast. A better understanding of these factors could lead to the development of medical therapies that are readily tolerated by older patients and prevent the need for potentially risky surgical intervention for the aging patient pool experiencing LUTD.

The aims of my project seek to first identify the contribution of the IL-4/IL-13 signaling axis to extracellular matrix (ECM) upregulation in prostate fibroblasts and demonstrate its dependence on JAK/STAT signaling. Next, I will explore the response of human prostate fibroblasts to β-sitosterol, a plant sterol isolated from palmetto sawgrass which is the active ingredient in most commercially available prostate supplements. Finally, I will investigate the potential role of a newly explored class of RNA splicing isoforms, circular RNA (circRNA), in the regulation of fibrotic processes in response to IL-4/IL-13.

With such a large gap in treatment options for patients suffering from LUTD, there is a significant clinical need for better therapies to be developed. Since the patient population suffering from this disease is older, the surgical interventions that are currently used to treat LUTD have a much higher risk of collateral injury. By identifying the molecular mechanisms that underly the fibrotic condition of aging and inflammation in the prostate, my project could benefit patients by saving them both the pain and financial hardship associated with BPH/LUTD.

Comments

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