{"id":{"repo_id":"ohiolink","oai_identifier":"oai:etd.ohiolink.edu:case1354917428"},"canonical_url":"https://search.dev.ndltd.org/etd/ohiolink/oai:etd.ohiolink.edu:case1354917428","repository":{"repo_id":"ohiolink","name":"OhioLINK","base_url":"https://etd.ohiolink.edu/acprod/odb_etd/ws/oai/oai"},"display":{"title":"Loss of Mismatch Repair in the Aging Human Hematopoietic Stem Cell","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Kenyon, Jonathan Dallas"],"institution":"Case Western Reserve University School of Graduate Studies","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Pathology","degree_department":null,"school":null,"contributors":["Gerson, Stanton","Tartakoff, Alan"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-03-08","date_published":"2013-03-08","updated_at":"2026-07-24T03:35:52Z","subjects":["Bioinformatics","Biology","Biomedical Research","Cellular Biology","Genetics","Gerontology","Health","Molecular Biology","Aging","Adult Stem Cells","DNA Repair","Mismatch Repair"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. 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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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.137","6.17 MB"]},{"key":"dc:title","label":"Title","values":["Loss of Mismatch Repair in the Aging Human Hematopoietic Stem Cell"]}]}],"canonical_facts":{"dc:contributor":["Gerson, Stanton","Tartakoff, Alan"],"dc:creator":["Kenyon, Jonathan Dallas"],"dc:date":["2013-03-08"],"dc:description":["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. 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