Author ORCID Identifier
https://orcid.org/0000-0001-8650-1225
Date of Award
Summer 2026
Document Type
Thesis (Ph.D.)
Department or Program
Molecular and Systems Biology
First Advisor
Michael L. Whitfield
Abstract
This thesis advances heterogeneity as the central barrier both to interpreting therapeutic response and to identifying the molecular regulators that drive fibrosis in systemic sclerosis (SSc). In SSc, heterogeneity is manifest at every level at which the disease can be measured: clinically, in the variable extent of skin and organ involvement; molecularly, in the distinct gene-expression programs that distinguish otherwise comparable patients; and cellularly, in the diverse fibroblast populations from which the fibrotic signal ultimately arises.
Leveraging longitudinal skin transcriptomics from a large cohort treated with mycophenolate mofetil (MMF), the first study demonstrates that intrinsic molecular subtypes are dynamic rather than fixed, that their trajectories track clinical change and help distinguish genuine treatment response from spontaneous regression, and that MMF is associated with a coordinated shift toward a normal-like molecular state. The second study establishes RUNX1 as a previously unrecognized transcription factor in SSc dermal fibrosis, demonstrating that its expression is epigenetically dysregulated through hypomethylation, enriched within specific profibrotic fibroblast subpopulations, and functionally required for fibroblast activation, contraction, proliferation, and matrix production. The third study extends this work into mechanistic and physiologically relevant systems - 3D skin equivalents, multicellular models, and in vivo murine fibrosis - revealing RUNX1 as a context- and state-dependent regulator governed by tissue architecture, cellular milieu, injury severity, and disease stage rather than a simple on-off switch.
Collectively, these findings demonstrate that deconstructing the heterogeneity of systemic sclerosis, from patient subtypes to the pathogenic fibroblasts that drive disease, is essential for interpreting therapeutic response, for identifying the molecular regulators of fibrosis, and ultimately for advancing precision medicine in SSc.
Recommended Citation
Parvizi, Rezvan, "Deconstructing Systemic Sclerosis Heterogeneity: from Patient Subtypes to Pathogenic Fibroblasts" (2026). Dartmouth College Ph.D Dissertations. 543.
https://digitalcommons.dartmouth.edu/dissertations/543
