Author ORCID Identifier


Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Harry Karmouty-Quintana and Shervin Assassi

Committee Member

Jennifer Bailey

Committee Member

Jeffery Chang

Committee Member

Jeffery Frost

Committee Member

Edgar T. Walters

Committee Member

Mikhail Kolonin


Systemic sclerosis (SSc; scleroderma) is a chronic systemic autoimmune and connective tissue disorder characterized by vasculopathy, autoimmune phenomena, and widespread fibrosis. Skin thickening and tightening is the cardinal feature of SSc and is responsible, in part, for the considerable morbidity of this disease. There are currently no targeted treatments for skin manifestations in SSc, primarily due to our fragmented understanding of its pathophysiologic mechanisms. In PART I, we report a previously unappreciated link between aberrant expression of the developmental gene sine oculis homeobox homolog 1 (SIX1) in skin-associated adipocytes in SSc skin and the early loss of dermal white adipose tissue (DWAT). We validated the mammalian expression of Six1 in murine dermal adipocytes, and using two transgenic models lacking Six1, we demonstrate that Six1 plays a vital role in the fate of dermal adipocytes in the context of skin fibrosis. In PART II, we discuss a novel finding that a higher circulating neutrophil-to-lymphocyte ratio predicts declining lung function over time and increased mortality in SSc. We propose that higher peripheral blood neutrophil and lower lymphocyte counts might reflect pathological immune processes in SSc and serve as markers for more severe disease. Together, this work uses distinct approaches to address two under-studied components of SSc pathophysiology, both of which have novel clinical and translational implications warranting further study.


SSc, scleroderma, fibrosis, adipose, neutrophil, dermatology, rheumatology, autoimmune



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