The long term goal of this proposal is to elucidate mechanisms which are responsible for the age-related changes and for the intrinsic genetic control of the function of hematopoietic stem cells. Our preliminary data show that the activity of a progenitor cell associated autocrine loop involving transforming growth factor-beta (TGF-beta), a potent inhibitor of hematopoiesis is subject to age-related changes and is genetically determined. Therefore, we hypothesize that the inhibitory autocrine loop is induced during senescence and is one of the mediators of the developmentally regulated decrease in proliferative and repopulation capacity of stem cells, thereby protecting stem cells from critical telomere shortening. Furthermore, we hypothesize that genetically determined functional variation in the TGF-beta system is one of the factors responsible for the variation in the in vivo behavior of the stem cells among mouse strains.
The specific aims of this proposal are the following: 1. In vitro molecular and functional studies of the autocrine TGF-beta look in mice: Studies will be undertaken to determine at which molecular level (production, activation, secretion, signal transduction) the autocrine TGF- beta loop differs among mouse strains. The evolution of the autocrine (TGF-beta), loop with age will be further investigated in several inbred mouse strains. 2. To study the role of the autocrine TGF-beta loop in the biology of the murine hematopoietic system in vivo: Approaches will be used where the repopulating potential of stem cells deficient in components of the autocrine TGF-beta loop will be assessed. 3. Mapping strain-dependent differences in the autocrine TGF-beta loop. Gene mapping will be performed using appropriate sets of recombinant inbred strains.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG016327-01A2
Application #
6126543
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Fuldner, Rebecca A
Project Start
2000-04-15
Project End
2005-03-31
Budget Start
2000-04-15
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$364,000
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Snoeck, Hans-Willem (2013) Aging of the hematopoietic system. Curr Opin Hematol 20:355-61
Avagyan, Serine; Aguilo, Francesca; Kamezaki, Kenjiro et al. (2011) Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-*2 and FLT3 in hematopoiesis. Blood 118:6078-86
Aguilo, Francesca; Avagyan, Serine; Labar, Amy et al. (2011) Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood 117:5057-66
Green, Michael D; Chen, Antonia; Nostro, Maria-Cristina et al. (2011) Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat Biotechnol 29:267-72
Kumar, Ritu; Avagyan, Serine; Snoeck, Hans-Willem (2010) A quantitative trait locus on chr.4 regulates thymic involution. J Gerontol A Biol Sci Med Sci 65:620-5
Yvan-Charvet, Laurent; Pagler, Tamara; Gautier, Emmanuel L et al. (2010) ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328:1689-93
Fossati, Valentina; Kumar, Ritu; Snoeck, Hans-Willem (2010) Progenitor cell origin plays a role in fate choices of mature B cells. J Immunol 184:1251-60
Kumar, Ritu; Fossati, Valentina; Israel, Mason et al. (2008) Lin-Sca1+kit- bone marrow cells contain early lymphoid-committed precursors that are distinct from common lymphoid progenitors. J Immunol 181:7507-13
Avagyan, Serine; Glouchkova, Ludmila; Choi, Juhyun et al. (2008) A quantitative trait locus on chromosome 4 affects cycling of hematopoietic stem and progenitor cells through regulation of TGF-beta 2 responsiveness. J Immunol 181:5904-11
Kumar, Ritu; Langer, Jessica C; Snoeck, Hans-Willem (2006) Transforming growth factor-beta2 is involved in quantitative genetic variation in thymic involution. Blood 107:1974-9

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