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Dr. Mare Cudic conducts research in the fields of cancer, obesity-linked diseases and drug delivery systems. Her cancer research targets the cell-surface carbohydrates and their binding proteins (lectins) to suppress metastasis. Dr. Cudic’s drug delivery studies use liposome-based nanomedicine to deliver anticancer drugs. In addition, Dr. M. Cudic investigates the role of adiponectin in suppressing type 2 diabetes, obesity, and atherosclerosis.
A major goal in developing new cancer chemotherapeutics is to identify and target biological processes that distinguish malignant from normal cells. One such target is the glycosylation of proteins, which is known to change with the onset of cancer. Recently, it was demonstrated that a β–galactoside-specific lectin expressed on endothelial cells, galectin-3, interacts with Thomsen-Friedenreich (TF) antigen (core I structure: galactose-β-1,3-N-acetylgalactosamine) of the cancer-associated MUC1 glycoprotein. This interaction promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. The goal of our research is to design inhibitors of galectin-3 that can suppress cancer cell adhesion, migration, and invasion, thereby reducing formation of metastases.
A second goal of our research is to design and prepare novel functionalized liposomes to target cancers that use carbohydrate recognition by lectins to metastasize. The use of integrated nanotherapeutic systems (e.g., theranostic nanomedicine) has emerged as a novel and promising therapeutic approach. Most nanomedicine systems have low therapeutic efficacy due to the so-called “passive targeting” concept. To minimize adverse effects, our research efforts are focused on enhancing the nanomedicine’s selectivity by utilizing the “active targeting" approach.
Adiponectin is an adipocyte-secreted peptide hormone that has demonstrated insulin-sensitizing properties. In addition, adiponectin has many beneficial effects on obesity-related metabolic and cardiovascular dysfunctions. Adiponectin is predominantly present in the circulation as oligomeric complexes; by contrast, the monomeric form of adiponectin has never been detected under native conditions. Evidence from clinical, genetic, and animal studies increasingly suggest that oligomerization represents a key mechanism for regulation of the multiple biological activities of adiponectin. Posttranslational modifications (PTMs) within the collagenous domain of adiponectin, including hydroxylation of proline, and hydroxylation and glycosylation of lysine, have recently been shown to correlate with adiponectin multimerization and secretion. The specific goals of this research project are to elucidate further the role of adiponectin PTMs, particularly glycosylation, in oligomer assembly, and to elucidate the susceptibility of adiponectin to proteolytic cleavage.
Dr. Mare Cudic started her research career at the University of Zagreb, Croatia, where she obtained a Ph.D. in organic chemistry in 1996. The focus of her Ph.D. thesis was the synthesis of glycoconjugates of leucine- and methionine-enkephalins, endogenous opioid peptides in order to gain insights into alterations in receptor selectivity induced by glycosylation. Dr. Cudic was awarded the prestigious European Peptide Society Award for Young Scientists in 1994 to further explore structure activity relationship studies of enkephalin glycopeptides analogs.
Dr. Cudic has held two postdoctoral fellow positions in Paris, France. In the laboratory of Claire Ducrocq at the National Center for Scientific Research, Institute for Natural Compounds, she assessed the reactivity of nitric oxide and its higher oxides (NO2, N2O3, and peroxynitrite) toward biologically active peptides and some currently used drugs. In the laboratory of Prof. Jean-Marie Lehn, 1987 Nobel Prize Laureate, she was engaged in the design and synthesis of novel nonviral gene transfer agents based on amino carbohydrates. Dr. Cudic continued her postdoctoral training in the USA at the Wistar Institute, Philadelphia, in the laboratory of Dr. Laszlo Otvos in cancer glycobiology, glycoimmunology and antimicrobial drug development.
In 2003, she was recruited by Dr. Gregg Fields to the Center of Excellence in Biomedical and Marine Biotechnology at Florida Atlantic University, Boca Raton, Florida. As a part of the Center, Dr. Cudic was engaged in the synthesis of non-proteinogenic amino acid γ-hydroxyvaline (γ-HyVal) found for the first time in the peptide sequence of a novel conopeptide that belongs to the class of valuable therapeutic agents for the treatment of a variety of neurologically related diseases. In addition, Dr. Cudic continued to explore the biological role of glycans in protein structure and function. Under the mentorship of Dr. Fields, she synthesized triple-helical models of collagen containing hydroxylated and monoglycosylated hydroxylysine (Hyl) moieties to study enzymes involved in collagen post-translational modification, the effects of glycosylation on cell recognition and signaling, and collagen fibril formation.
Dr. Cudic joined Torrey Pines Institute for Molecular Studies in July 2010 as an Assistant Member.