Loss of Mismatch Repair in the Aging Human Hematopoietic Stem Cell

All organisms undergo complex changes over time. These changes, associated with an increasing incidence of disease and decreased functional capacity, are collectively referred to as aging. To understand this process, to prolong functional capacity, and to prevent the expensive and debilitating diseases associated with increased age is an ongoing focus of scientific study. In the introduction chapter of this dissertation, I present a philosophical argument suggesting aging and age related diseases are a result of intraorganismal genetic change, as a result of failed DNA damage repair, in the adult stem cell (ASC) population. The hematopoietic stem/progenitor cell (HPC) is a well characterized example of ASCs. In second and third chapters I show evidence of age related accumulated genetic instability and epigenetic loss of the DNA mismatch repair (MMR) protein MLH1 expression in the HSCs obtained from healthy normal donors. Based on this observation ASCs cannot, as previously thought, be truly immune to the effects of the aging process, nor is it likely these cells possess infinite expansion potential. In the last chapter of this manuscript, I highlight the impact of these findings and suggest a model of HPC aging which implies age related dysfunction of HSCs is the result of acquired genetic and epigenetic changes incurred over a lifetime.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Pathology

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Kenyon, Jonathan Dallas

Contributors dc:contributor

• Gerson, Stanton
• Tartakoff, Alan

• Bioinformatics
• Biology
• Biomedical Research
• Cellular Biology
• Genetics
• Gerontology
• Health
• Molecular Biology
• Aging
• Adult Stem Cells
• DNA Repair
• Mismatch Repair

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1354917428

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1354917428