Saturday, April 27, 2024
4/27/2024
The Role of BHLHB2 in Scleroderma-Associated Lung Fibrosis Scleroderma/Systemic Sclerosis (SSc) is a fibrosing multi-system rheumatic disease associated with excessive deposition of extracellular matrix (ECM) components such as collagen and fibronectin. The predominant and fatal complication of SSc is Pulmonary Fibrosis (PF), for which current treatments are marginally effective. IL-6 is a pro-inflammatory and pro-fibrotic cytokine produced in excess in SSc fibroblasts. Likewise, insulin-like growth factor (IGF)-II, a member of the IGF family, is produced in excess in SSc fibroblasts and is implicated in the development of pulmonary fibrosis. Our lab has shown that IGF-II levels are increased in both SSc lung tissues and the primary fibroblasts derived from them, and that IGF-II induces a fibrotic response in normal lung (NL) fibroblasts. IGF-II increases levels of collagen, fibronectin, and the pro-fibrotic transforming growth factor beta-2 (TGF¿2). In this application, we demonstrate that IL-6 increases IGF-II mRNA levels. Microarray analysis of IGF-II-treated NL fibroblasts revealed increased expression of the Basic Helix-Loop-Helix transcription factor family member, BHLHB2, a known regulator of the circadian rhythm, adipogenesis, and fibroblast autophagy. Our preliminary data further show that both IL-6 and IGF-II increase nuclear BHLHB2 levels in NL fibroblasts. We show that BHLHB2 activation is a common link between, and downstream mediator for several profibrotic agents: TGF¿, IL-6 and IGF-II. Silencing BHLHB2 downregulated IGF-II. IGF-II induced BHLHB2 via signaling through the Insulin Receptor. Thus, our central hypothesis is that BHLHB2 contributes to the progression of Scleroderma-associated Lung Fibrosis by increasing levels of ECM genes. Our goal is to delineate the role of BHLHB2 in the development of lung fibrosis in Systemic Sclerosis by (1) identifying the mechanism by which IL- 6 and IGF-II regulate BHLHB2, comparing differentially-expressed genes in single cell RNASeq of IGF-II-and IL- 6 stimulated normal lung and (2) elucidating the role of BHLHB2 in lung fibrosis. These aims are consistent with the National Heart Lung and Blood Institute’s mission since they will provide important fundamental basis for addressing translational aspects of the interaction between genetic dysregulation due to IGF-II and development of SSc-associated PF. We envision that our work will provide a rationale for a therapy to block IL-6 and IGF-II function concomitantly to halt the progression of lung fibrosis in SSc. Since SSc-PF is characterized by activation of common fibrotic pathways and increases in ECM components (collagen, fibronectin), which are also increased in different diseases characterized by lung fibrosis, our findings may have wider implications for lung fibrosis associated with other diseases. In addition to facilitating a deeper understanding of mechanisms of SSc-PF, this proposal provides Adegboyega Timothy Adewale with a rigorous training under the mentorship of Dr. Carol Feghali-Bostwick and equips him with cutting-edge techniques to develop as an astute and skillful physician- scientist.
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