Date of Award
Department or Program
Quantitative Biomedical Sciences
Michael L. Whitfield
Patricia A. Pioli
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and internal organs, vascular abnormalities, and autoantibody formation. The etiology of SSc is unknown, though the disease is thought to arise in genetically predisposed individuals after exposure to an environmental factor. There are few FDA approved disease modifying medications available to treat SSc.
The express aims of this dissertation are tripart. First, we aimed to validate a 3D tissue model known as the self-assembled skin equivalent (saSE) model. Second, we sought to describe the geographic distribution of SSc in a US Medicare population to better understand potential environmental factors contributing to SSc. Finally, we observed an upregulation of fibrotic signaling in innate immune and collagen producing cells after exposure to 17β-estradiol.
A focus of this dissertation was to validate and demonstrate the functional relevance of a 3D tissue model of SSc. We constructed healthy control and SSc saSE tissues, dissociated them, and conducted single cell RNA-sequencing on them. Analysis of this study revealed fibroblast heterogeneity in the saSE tissues.
In the second chapter of this work, we describe the geographic distribution of Other Connective Tissue Disease (OCTD) and SSc in a United States (US) Medicare beneficiary population. We discovered clusters of OCTD and SSc in several states. After overlaying these clusters with superfund site locations we discovered that many of these statistically significant clusters are located in or around superfund sites.
We noted in our Medicare study as well as in previously published literature that SSc exhibits a female sex skew. In the third chapter of this thesis, we observe the impacts of 17β-estradiol, a female sex hormone, on MØ and fibroblast gene expression. We discovered that 17β-estradiol attenuates inflammatory signaling and induces fibrotic signaling in MØ and fibroblasts. We believe that estrogens may be contributing to continued fibrotic signaling in SSc.
These studies span molecular and population approaches to understanding this complex disease. Though much is required to establish treatments for and mechanisms leading to SSc, we are confident that these projects are the beginning of a path to understand how to treat SSc.
Kosarek, Noelle N., "Impacts of Population Level Environmental Contaminants, Sex Hormones, and Fibroblast Cell Subsets on Systemic Sclerosis (SSc)" (2022). Dartmouth College Ph.D Dissertations. 120.