Author ORCID Identifier

https://orcid.org/0000-0002-3015-4030

Date of Award

Summer 7-30-2024

Document Type

Thesis (Ph.D.)

Department or Program

Molecular and Systems Biology

First Advisor

Michael L. Whitfield, Ph. D.

Second Advisor

H. Robert Frost, Ph. D.

Third Advisor

Patricia A. Pioli, Ph. D.

Abstract

Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by dermal and internal organ fibrosis, including heart, lungs, and gastrointestinal tract, and autoantibody formation. Although disease etiology is currently unknown, like other autoimmune diseases, SSc likely develops due to environmental factor exposure in genetically susceptible individuals. Fibrotic diseases are notoriously difficult to treat. Coupled with the autoimmune aspect, SSc is difficult to study scientifically due to the lack of complex disease models that can recapitulate the immune-fibrotic axis of the disease. Due to this, there are only two FDA approved medical treatments for SSc approved for symptomatic treatment of SSc interstitial lung disease (SSc ILD).

Gene expression heterogeneity is seen within patients with SSc when comparing microarray or RNA-seq data. We have identified four reproducible gene expression subsets replicated across multiple datasets. The inflammatory subset, with upregulated gene expression pertaining to the immune system and inflammatory related genes. The fibroproliferative subset, with upregulation of extracellular matrix and cell cycle related genes. The limited subset, which consists solely of limited cutaneous SSc patients, and the normal-like subset, which is comprised of SSc patients clustering alongside healthy controls.

In the second chapter of this thesis, I describe the ability to use gene expression analyses to identify biologically relevant pathways specific to SSc patient subsets for potential therapeutic targeting. Using data from SSc cohorts and Connectivity Map, we found multiple small molecule inhibitors, which we tested in our 3D tissue culture system. SSc tissues treated with these molecules showed disease-specific effects, particularly thinner tissue growth, when compared to healthy control tissues.

In chapter three, studies focused on identifying commonalities between SSc and Morphea patients. Morphea, also known as localized scleroderma, is a fibrotic disease resulting in fibrotic patches of skin. Contrasting SSc, affected and unaffected skin showed different gene expression. Morphea patients clustered with SSc patients and had striking similarities in inflammatory gene expression signatures.

These studies were performed to elucidate mechanisms of SSc that may lead to potential therapeutic targeting. More complex models will allow for safer, more targeted and biologically relevant therapeutic testing, which is imperative to curing complex diseases.

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