Date of Graduation

Spring 2019

Degree

Master of Science in Cell and Molecular Biology

Department

Biomedical Sciences

Committee Chair

Amanda C. Brodeur

Abstract

Mucopolysaccharidosis type I (MPS I) is a rare, autosomal recessive disorder caused by the deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Absence of IDUA results in the accumulation of dermatan and heparin sulfate and ultimately causes multi-system dysfunction. The most severe form of MPS I is Hurlers syndrome, a rapidly progressive disorder that, if left untreated, is fatal. Current treatment options for diagnosed individuals includes hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). These treatments are able to ameliorate the majority of symptoms with the exception of the bone phenotype. This investigation aimed to further characterize the bone phenotype in a knock- in mouse model (IDUA-W392X), containing a nonsense mutation analogous to the IDUA mutation commonly found in human Hurlers syndrome patients. To accomplish this the organic portion of the bone was analyzed. The most abundant bone matrix protein, type I collagen, was indirectly quantified in wild type, heterozygous, and mice without IDUA activity. Findings indicate significantly elevated type I collagen content and bone mass in male IDUA-W392X mice. In order to inspect the extent of IDUA deficiency on bone resorbing osteoclasts, a protocol was establish to examine their activity. Previous investigations have indicated impaired bone remodeling and a decrease in expression of biomarkers for osteoclast differentiation. This study examined protein localization of RANKL, the stimulus responsible for initiating resorption, through immunohistochemical staining of decalcified bone tissue. Finally, this study further defined the rights and protections of children involved clinical research. This was accomplished through developing the discussion of maintaining patient autonomy, retaining open communication between clinicians and patients, and the process of consenting to clinical research.

Keywords

Mucopolysaccharidosis, Hurler syndrome, bone remodeling, type I collagen, hydroxyproline, osteoclast, immunohistochemistry, pediatric bioethics

Subject Categories

Bioethics and Medical Ethics | Cell Biology | Molecular Biology

Copyright

© Anna Marie McWoods

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