description) The overall objective is to follow homing of the most primitive hemopoietic stem cells (PHSC) from liver to marrow at birth, and after adult marrow grafts. PHSC repopulate both myeloid and lymphoid compartments continuously during at least half the life span, so their functions are vital to long term health. After homing, PHSC number and function will be directly analyzed by long term competitive repopulation and competitive dilution in vivo using newly produced congenic donor markers, avoiding enrichment, tissue culture, or retroviral marking, manipulations that might affect PHSC.
Aim 1 tests induced mutations affecting putative homing and regulatory genes: ICAM-1, TNFRp55, VCAM-1,E- and P- selectin, integrins alpha 4, alpha 5, and beta 2. Combinations will be tested first, as homing may be redundant, needing combinations of mutant adhesion molecules to show effects. Similar effects on: (1) PHSC migration from fetal and newborn liver to marrow; and (2) adult marrow grafting would suggest that migration and grafting are controlled by the same genes.
Aim 2 tests whether strain differences in PHSC function are intrinsic in recipient homing or in donor PHSC. Fetal and adult PHSC will be compared in B6, BALB, B6xBALBF1, and NOD-scid/scid recipients, controlling for both immune responses and natural resistance. PHSC function similar to recipient rather than donor would suggest that stromal homing and regulatory genes control the strain effects.
Aim 3 compares PHSC damage due to transplantation in irradiated, chemotherapy treated or W-anemic recipients, as these treatments may affect PHSC homing and function. Also, PHSC damage due to homing will be distinguished from damage due to proliferation or handling by comparing PHSC in irradiated mice that have most or little marrow shielded , with PHSC in grafted recipients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058705-02
Application #
2771601
Study Section
Special Emphasis Panel (ZHL1-CSR-J (M1))
Project Start
1997-09-15
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Chen, J; Astle, C M; Muller-Sieburg, C E et al. (2000) Primitive hematopoietic stem cell function in vivo is uniquely high in the CXB-12 mouse strain. Blood 96:4124-31
Chen, J; Astle, C M; Harrison, D E (2000) Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol 28:442-50