All ETDs from UAB

Advisory Committee Chair

Thomas M Ryan

Advisory Committee Members

Anupam Agarwal

Peter D Burrows

Peter J Detloff

Tim M Townes

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In this dissertation we describe knockin mouse models for the study of human hemoglobin disorders. These knockin human globin genes, in contrast to transgenes, replace the adult mouse globin genes, remain under control of endogenous mouse globin enhancer sequences and are inherited in a manner identical to globin alleles in man. Starting with various knockin alleles composed of unique human alpha, beta and gamma globin gene sequences, we evaluate several allele combinations towards our goal of generating improved models of thalassemia and sickle cells disease. We show that humanized knockin mice complete a fetal to adult hemoglobin switch during postnatal development, similar to humans, allowing investigation of switching mechanisms. We demonstrate targeted repair of a beta thalassemia allele in mouse stem cells, with introduced human beta globin gene expression correcting their anemia. In fully humanized mice a single inactivated beta globin gene results in beta thalassemia minor, unlike previous mouse models but comparable to human trait patients. Within the context of sickle cell disease in humanized knockin mice we also investigate the role of alpha thalassemia to improve the hematological phenotype and increase survival independent of the role of fetal hemoglobin. In conclusion, humanized knockin mice faithfully model essential aspects of human hemoglobin disorders, advancing our fundamental understanding of their pathology and providing a platform to test novel therapies.

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