This project will help to clarify the pathogenesis of Alport syndrome and investigate a new strategy for treatment.
The first aim will be to study how type IV collagen folds around natural sequence interruptions, which exist benignly in the normal collagen sequence. Recombinant collagen will be used to study the effect of interruptions on folding kinetics by circular dichroism, trypsin susceptibility, fluorescence, and electron microscopy. A subset of natural interruptions is similar to the sequences created by glycine missense mutations that cause Alport syndrome.
The second aim will be to examine the differences between these interruptions and mutations in sequence, structure, and folding to provide insight into defective folding around mutations. Peptide and recombinant systems will be employed to obtain structural and kinetic information.
The third aim will be to test small molecule chaperones to determine whether they can correct folding defects caused by missense mutations.
Current treatments for the inherited kidney disease Alport syndrome do not prevent kidney failure, resulting in a need for transplantation and lifelong immunosuppressant medications. The goal of this research training plan is to improve understanding of how Alport syndrome mutations affect the folding of type IV collagen, and to test drugs that may improve treatment by improving folding.
|Hwang, Eileen S; Brodsky, Barbara (2012) Folding delay and structural perturbations caused by type IV collagen natural interruptions and nearby Gly missense mutations. J Biol Chem 287:4368-75|