Regulation of retinoid homeostasis by cellular retinol-binding protein, type 1
|University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2022.
|Retinoic acid (RA) is the main active metabolite of Vitamin A, an essential diet-derived nutrient. RA signaling regulates cell differentiation, proliferation and apoptosis. RA levels are tightly regulated throughout the body via the expression and activity of catabolic and biosynthetic enzymes, and chaperone proteins, including cellular retinol binding protein, type 1 (CRBP1). CRBP1 binds to retinol and retinal, protecting them from non-specific oxidation, and facilitating their delivery to the appropriate enzymes for RA biosynthesis. CRBP1 has been shown to be decreased in disease states that display dysfunctional proliferation and differentiation, including cancers. Reduction of CRBP1 levels directly correlates with reduction in RA and restoration of CRBP1 expression has been shown to increase RA levels and positively impact RA-dependent outcomes. Research on the role of CRBP1 in disease has been limited because of its low abundance and poor immunogenicity. We have developed a targeted, bottom-up proteomics approach for absolute CRBP1 quantitation in complex biological matrices and have utilized this assay to answer important biological questions regarding the role of CRBP1 in regulating RA and RA-mediated signaling. While proper RA homeostasis is essential for biological processes throughout the body, the research in this thesis has focused on its role in the small intestine, heart, and lung. In the small intestine, RA plays an essential role in regulating the gut immune response. In instances of cellular stress in the intestine, RA levels are decreased. We have employed our CRBP1 quantitative assay, along with retinoid metabolite quantitation and quantitative gene expression, to systemically probe the mechanism of disrupted retinoid signaling in intestinal disease via an in vitro model of the small intestine. Proper RA levels are also necessary for growth and development, including heart and lung morphogenesis, and have also been shown to be disrupted in many diseases, such as heart failure and lung cancer. Using a global CRBP1 knock-out mouse model, we have also explored the in vivo effect of loss of CRBP1 on retinoid signaling via multi-omics analysis. Together these studies will help further our understanding of the mechanisms and impact of CRBP1 loss in diseases of the intestine, heart, and lungs.
|Retinol-Binding Proteins, Cellular
|Regulation of retinoid homeostasis by cellular retinol-binding protein, type 1
|Kane, Maureen A.