bradley-hamilton@uiowa.edu
Mentor: Joseph Zabner, M.D.
Lab Room: 440 EMRB
Lab Phone: 319-335-7608

Understanding the functional implications of adeno associated viral capsid topologies

People with cystic fibrosis (CF) lack a functional transmembrane conductance regulator protein (CFTR), and have defective airway defense against bacteria. The resulting airway infections initiate a cascade of inflammation and airway wall remodeling that progressively injure the lungs and shorten lives. Adeno-associated virus (AAV) mediated gene therapy can correct this defect and prevent lung infections. Studies in humans have shown that aerosolized AAV2 is a safe, albeit inefficient vector for gene therapy. In recent years, directed evolution has produced different AAV2 serotypes capable of delivering their genetic cargo with greater efficacy. Employing a porcine model genetically engineered to recapitulate the human CF phenotype, our investigations focus on understanding the functional significance of specific amino acid substitutions in the viral capsid, improving viral vectors for the purpose of gene therapy, and determining whether AAV-CFTR can be used to cure CF lung disease.

Hamilton BA, Li X, Pezzulo AA, Abou Alaiwa MH, Zabner J. Polarized AAVR expression determines infectivity by AAV gene therapy vectors. Gene Ther. 2019 Apr 8. doi: 10.1038/s41434-019-0078-3. [Epub ahead of print] PubMed PMID:30962536.

Zepeda-Orozco D, Wen HM, Hamilton BA, Raikwar NS, Thomas CP. EGF regulation of proximal tubule cell proliferation and VEGF-A secretion. Physiol Rep. 2017 Sep;5(18). pii: e13453. doi: 10.14814/phy2.13453. Epub 2017 Sep 27. PubMed PMID: 28963126; PubMed Central PMCID: PMC5617933.

Radley JJ, Anderson RM, Hamilton BA, Alcock JA, Romig-Martin SA. Chronic stress-induced alterations of dendritic spine subtypes predict functional decrements in an hypothalamo-pituitary-adrenal-inhibitory prefrontal circuit. J Neurosci. 2013 Sep 4;33(36):14379-91. doi: 10.1523/JNEUROSCI.0287-13.2013. PubMed PMID: 24005291; PubMed Central PMCID: PMC3761048.