Hematopoiesis involves the tightly coordinated process of blood cell production and is maintained by a small number of hematopoietic stem cells (HSCs). Compared to the young, the elderly show a substantial decline of baseline functions and adaptive capacity in various tissues and organs, including the hematopoietic system. It is assumed that these changes in hematopoiesis with age comprise one of the underlying causes for anemia and reduced immune function in the elderly, especially under stress. Resolving the number of HSCs and their progeny that actively contribute to hematopoiesis and tracking the contribution of individual HSCs to each of the different blood cell lineages is an important step to determine the cellular basis for decreased efficiency in tissue homeostasis. The primary goal of this study is to determine, on a clonal level, the cellular and molecular basis for decreased efficiency in hematopoiesis upon aging, with the long-term goal to translate this knowledge into therapies to ameliorate or even revert unwanted age-associated phenotypes in the hematopoietic system. We will use the novel technology of clonal barcoding of individual murine HSCs by short-term (4 hours) transduction (ex vivo) with self-inactivating lentiviral vectors to individually mark a multitude of HSCs to determine clonality, lineage determination and cell turnover in the hematopoietic system and the changes in these parameters associated with aging.

Public Health Relevance

Compared to the young, the elderly show a substantial decline of baseline functions and adaptive capacity in various tissues and organs, including the hematopoietic system. In order to provide a more complete description of tissue homeostasis during aging, it is important to have quantitative lineage tracing used in the hematopoietic system for analyzing tissue maintenance and repair upon aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG040118-02S1
Application #
8522357
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Kohanski, Ronald A
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2012-08-15
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$38,250
Indirect Cost
$13,250
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Thielecke, Lars; Aranyossy, Tim; Dahl, Andreas et al. (2017) Limitations and challenges of genetic barcode quantification. Sci Rep 7:43249
Brown, Andreas; Pospiech, Johannes; Eiwen, Karina et al. (2017) The Spindle Assembly Checkpoint Is Required for Hematopoietic Progenitor Cell Engraftment. Stem Cell Reports 9:1359-1368
Kumar, Sachin; Geiger, Hartmut (2017) HSC Niche Biology and HSC Expansion Ex Vivo. Trends Mol Med 23:799-819
Guidi, Novella; Geiger, Hartmut (2017) Rejuvenation of aged hematopoietic stem cells. Semin Hematol 54:51-55
Guidi, Novella; Sacma, Mehmet; Ständker, Ludger et al. (2017) Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J 36:840-853
Akunuru, Shailaja; Geiger, Hartmut (2016) Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells. Trends Mol Med 22:701-12
Sampson, Leesa L; Davis, Ashley K; Grogg, Matthew W et al. (2016) mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. FASEB J 30:1263-75
Moehrle, Bettina M; Geiger, Hartmut (2016) Aging of hematopoietic stem cells: DNA damage and mutations? Exp Hematol 44:895-901
Chang, Kyung Hee; Nayak, Ramesh C; Roy, Swarnava et al. (2015) Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT?R and cytoskeletal dysregulation. Nat Commun 6:5914
Denkinger, Michael D; Leins, Hanna; Schirmbeck, Reinhold et al. (2015) HSC Aging and Senescent Immune Remodeling. Trends Immunol 36:815-24

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