Author ORCID Identifier
0000-0001-5149-3966
Date of Graduation
5-2023
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
Abstract
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.
Keywords
SSc, scleroderma, fibrosis, adipose, neutrophil, dermatology, rheumatology, autoimmune
Included in
Bioinformatics Commons, Cell Biology Commons, Cellular and Molecular Physiology Commons, Dermatology Commons, Developmental Biology Commons, Immune System Diseases Commons, Immunity Commons, Laboratory and Basic Science Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Rheumatology Commons, Skin and Connective Tissue Diseases Commons