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 #
5R01AG040118-03
Application #
8514463
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Kohanski, Ronald A
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$325,316
Indirect Cost
$112,691
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zheng, Yi; Geiger, Hartmut (2014) HSPCs get their motors running for asymmetric fate choice. Cell Stem Cell 14:1-2
Geiger, Hartmut; de Haan, Gerald; Florian, M Carolina (2013) The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13:376-89
Geiger, Hartmut; Zheng, Yi (2013) Cdc42 and aging of hematopoietic stem cells. Curr Opin Hematol 20:295-300
Zhou, Xuan; Florian, Maria Carolina; Arumugam, Paritha et al. (2013) RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors. J Exp Med 210:2371-85
Florian, Maria Carolina; Nattamai, Kalpana J; Dorr, Karin et al. (2013) A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503:392-6