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Development of synthetic glycosaminoglycan glycoconjugates and their application to manipulate cellular signaling events

  • Author(s): Trieger, Greg
  • Advisor(s): Godula, Kamil
  • et al.
No data is associated with this publication.
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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This item is under embargo until January 8, 2021.