The aging process is associated with deterioration of the stem cell pool leading to organ failure and dysfunction. Animal models indicate a critical role for DNA repair in the maintenance of the hematopoietic stem cell phenotype. For instance, loss of mismatch repair or double strand break end-joining leads to a competitive repopulation defect and gradual stem cell failure. In mice defective in the ATM gene, and nucleotide excision repair, hematopoietic stem cell dysfunction has also been observed. Likewise, purified hematopoietic stem cells overexpress the mismatch repair protein, MSH-2 and the DNA repair scaffold, XRCC-1. As humans age, the stem cell phenotype changes, with gradual loss of stem cell numbers, regenerative potential and stress response. This proposal will evaluate the hypothesis that loss of genomic stability is an inexorable part of the aging process and is measurable by examining DNA repair pathways and function leads to loss of the stem cell phenotype, loss of regeneration potential and loss of appropriate stress responses. Clinical syndromes that accelerate during aging including anemia, marrow failure yielding mono and pancytopenia, immune dysregulation, myelodysplastic syndromes and leukemias may all have as a common etiology progressive loss of DNA repair capacity in hematopoietic stem cells, as has been observed in animal models. This proposal will develop multiplex assays of a broad range of DNA repair proteins, perform careful assessment of Hematopoietic Stem Cell phenotype and function, and optimize microassays of DNA repair processes in freshly isolated, purified Hematopoietic Stem Cells before and after DNA damage perturbation from the aging population in the decades of 50 to 90. These studies will serve as the prototype with which to analyze normal aging and the diseases associated with aging of hematopoietic stem ceils. Furthermore, these processes undoubtedly affect other tissue stem cells and these approaches may have broad application across stem cell types. These studies will provide the basis to further analysis of DNA repair processes during the aging of stem cells to identify stem cell deficit disorders, response to chemotherapy and other stresses of hematopoietic stem cells land the relation ship between DNA repair processes and stem cell function as measured by conventional and novel assays developed under this RFA.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024916-02
Application #
6949026
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
Program Officer
Dutta, Chhanda
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$323,480
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kenyon, Jonathan; Nickel-Meester, Gabrielle; Qing, Yulan et al. (2016) Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing. Int J Stem Cell Res Ther 3:
Desai, Amar; Webb, Bryan; Gerson, Stanton L (2014) CD133+ cells contribute to radioresistance via altered regulation of DNA repair genes in human lung cancer cells. Radiother Oncol 110:538-45
Qing, Yulan; Lin, Yuan; Gerson, Stanton L (2012) An intrinsic BM hematopoietic niche occupancy defect of HSC in scid mice facilitates exogenous HSC engraftment. Blood 119:1768-71
Kenyon, Jonathan; Fu, Pingfu; Lingas, Karen et al. (2012) Humans accumulate microsatellite instability with acquired loss of MLH1 protein in hematopoietic stem and progenitor cells as a function of age. Blood 120:3229-36
Kenyon, Jonathan; Gerson, Stanton L (2007) The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res 35:7557-65
Liu, Lili; Gerson, Stanton L (2006) Targeted modulation of MGMT: clinical implications. Clin Cancer Res 12:328-31