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Development of synthetic glycosaminoglycan glycoconjugates and their application to manipulate cellular signaling events
- Trieger, Greg
- Advisor(s): Godula, Kamil
Abstract
Growth factor signaling is a key determinant of cellular decisions ranging from
stem cell fate, to metabolic behavior. As such, gaining control over these signaling
events is of critical importance to the field of regenerative medicine, which is
continuously seeking novel means to tailor the cellular microenvironment to direct cells
towards medically advantageous outcomes. Heparan sulfate (HS) glycosaminoglycans
(GAGS) are sulfated polysaccharides found on the cell surface and in the extracellular
matrix which are responsible for the engagement of growth factors as well as growth
factor receptors as a means to spatiotemporally direct cell signaling events. Despite the
obvious potential associated with controlling HS GAG-growth factor interactions, HS
GAG-based approaches to manipulate cellular signaling has been minimal due to the
complex nature of this class of sulfated polysaccharides. Sulfated GAGs like HS have a
non-template driven synthesis, that is, their structure is not dictated by a genetic blue
print. During assembly, the GAGs undergo a series of sulfations, isomerizations, and
acetylations which give rise to their specific binding capacity, but it is this same
complexity that poses a significant hurdle for synthetic or chemoenzymatic approaches
geared at producing these structures for study and medical application. As a result,
novel approaches must be developed to hone control over cell signaling using GAGs
while circumventing the structural obstacle posed by the complexity of their structure. In
this dissertation, I present a variety of accessible methods for the preparation of
synthetic HS GAG glycoconjugates, and demonstrate their efficacy in several contexts.
In chapter 2, I introduce a HS GAG presenting, membrane incorporating, polymer which
utilizes a multivalent display of commercially available HS GAG disaccharides to exert
control over stem cell fate in a structure dependent manner. In chapter 3 I reveal the
role of HS GAG in the metabolic programming of adipocytes, and then apply these
polymers to enhance glucose clearance capacity in adipocytes, bearing implications for
the treatment of type 2 diabetes. In chapter 4, I developed a highly efficient “click”
based method for the conjugation of full length GAGs to protein substrates, and applied
these glycoconjugates to manipulate the growth rates of human stem cells from the
extracellular matrix. Finally, in chapter 5, I apply the synthetic polymers and protein
glycoconjugates to a cellular microarray, with the goal of miniaturizing cell based assays
for the high throughput study of glycomaterials.
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