Little is known about the mechanisms that regulate, at the cellular level, the process of hematopoietic cell self-renewal and differentiation, in particular during physiologic responses to stress, such as inflammation and infection. The overall objective of this project is to study the physiologic role of Notch receptors in maintaining bone marrow homeostasis, in particular during inflammatory stress. The main hypotheses to be tested in our study are: I) whether Notch activation favors the decision of self-renewal over differentiation at the stem and progenitor cell level, and 2) whether this represents an important regulatory function during bone marrow physiologic response to inflammation and infection. We hypothesize that Notch activation may balance the prodifferentiative effects of inflammatory cytokines, permitting expansion of the proliferating pool of progenitor cells required to respond to physiologic stress and preventing the stem cell pool from exhaustion.
Specific Aims : to test these hypotheses we plan to: (1) determine the impact of Notch gain-of function and (2) Notch loss-of function, on self-renewal and expansion potential of stem and progenitor cells; (3) evaluate the level of Notch pathway activation in BM cells during inflammatory stress; (4) determine the consequences of Notchi loss-of function during bone marrow response to inflammatory stress. Research Design and Methods: We will use different and complementary in vivo models: a) xenotransplantation experiments of human cells, engineered to express constitutive forms of Notch 1 or the ligand J2, will be carried out into NOD/S CID mice; b) transgenic mice engineered to express the Notch antisense will be used to evaluate the effects of Notch loss-of function; c) the """"""""mouse full skin thickness burn model"""""""" (sepsis model) will be used as a model of inflammation to evaluate BM response and Notch function. Significance: These studies are intended to yield insight into the physiologic mechanisms that regulate adult hematopoiesis. We believe that a better comprehension of these events is crucial for the understanding of the biology of hematopoietic disorders and essential for the development of novel therapeutic strategies, in particular those targeted to ex-vivo expansion of human hematopoietic stem cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068256-01
Application #
6395391
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Thomas, John
Project Start
2001-08-15
Project End
2005-07-31
Budget Start
2001-08-15
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$388,349
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Zhang, Huajia; Rodriguez, Sonia; Wang, Lin et al. (2016) Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88. Stem Cell Reports 6:940-56
Wang, Lin; Zhang, Huajia; Rodriguez, Sonia et al. (2014) Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-?B-dependent manner. Cell Stem Cell 15:51-65
Rodriguez, Sonia; Wang, Lin; Mumaw, Christen et al. (2011) The SKP2 E3 ligase regulates basal homeostasis and stress-induced regeneration of HSCs. Blood 117:6509-19
Carlesso, Nadia; Cardoso, Angelo A (2010) Stem cell regulatory niches and their role in normal and malignant hematopoiesis. Curr Opin Hematol 17:281-6
Rodriguez, Sonia; Chora, Angelo; Goumnerov, Boyan et al. (2009) Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood 114:4064-76
Fernandez, Luis; Rodriguez, Sonia; Huang, Hui et al. (2008) Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation. Exp Hematol 36:545-558
Christmas, Peter; Tolentino, Karine; Primo, Valeria et al. (2006) Cytochrome P-450 4F18 is the leukotriene B4 omega-1/omega-2 hydroxylase in mouse polymorphonuclear leukocytes: identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4. J Biol Chem 281:7189-96
Sarmento, Leonor M; Huang, Hui; Limon, Ana et al. (2005) Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation. J Exp Med 202:157-68
Christmas, Peter; Carlesso, Nadia; Shang, Haibo et al. (2003) Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter. J Biol Chem 278:25133-42