Date of Award

1-1-2020

Language

English

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College/School/Department

Department of Chemistry

Content Description

1 online resource (x, 89 pages) : illustrations (some color)

Dissertation/Thesis Chair

Alexander Shekhtman

Committee Members

Alan Chen, Jia Sheng

Keywords

Cell Physiology, Diabetes, Drug Screening, Mitochondrial Fusion MFN2, RAGE Diaphanous, Signal Transduction, Glycosylation, Insulin, Insulin antibodies, Cell receptors, Immunoglobulins

Subject Categories

Analytical Chemistry | Biochemistry | Chemistry

Abstract

The binding of advanced glycation end products (AGEs) to the receptor for advanced glycation end products (RAGE) is an important feature of the RAGE signaling pathway that plays a role in the pathogenesis of diabetes. Under high glucose concentration, RAGE expression increases immensely from the formation of a Schiff base by glucose bounded to lysine. This triggers an inflammatory and immune response and upregulates the expression of RAGE and causes an accumulation of AGEs in the body. As a result, this leads to the development of diabetes and other complications such as, atherosclerosis, nephrothapy, and retinopathy. To remedy AGE accumulation, therapeutic methods have been tested to block RAGE activation to prevent further intracellular signaling. Various molecules were analyzed as potential therapeutic candidates specifically, diaphanous (DIAPH1). The affinity of DIAPH1 to the cytoplasmic tail of RAGE (ctRAGE) and mitofusin protein MFN2 were studied extensively by means of Tryptophan Fluorescence, Nuclear Magnetic Resonance Spectroscopy (NMR), and Chemical cross-linking with mass spectrometry. These methods provided the topology of the molecules, the amino acid residues present in each, and its binding parameters to one each other. As a whole, the results provide a more in-depth understanding about the binding of DIAPH1 to ctRAGE and its effect in the RAGE signaling pathway.

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