This program brings together five hematopoiesis investigators who have been working collaboratively to address the fundamental question of how individual hematopoietic stem and progenitor cells (HSPC) are regulated to contribute to the production of blood under homeostatic and stress conditions. It creates a collective of complementary technologies developed in the investigator's laboratories to track individual clones in vivo and thereby to model how distinct clonal behaviors contribute to hematopoietic output under varying conditions. Furthermore, it employs innovative tools for manipulating specific molecular regulators of gene expression to test which molecules drive specific HSPC behaviors. These are tested in the context of inflammatory and genotoxic stress and are evaluated for their ability to alter the competitive relationship of normal HSPC with clones bearing blood disease associated alleles known to accumulate in the aging human. The cross comparison of models, species, time in development and molecular parameters (mRNA, meDNA, ncRNA, chromatin state) shared through an established common database and analytic tools provide a uniquely powerful means of defining with high resolution the process of hematopoiesis. By providing a mechanism to sustain interaction, share data and techniques and create a forum for resolution of conflicting data, this PO1 will facilitate the creation of a hematopoiesis `roadmap' whereby interventions at specific molecular waypoints can modulate blood cell production to enhance hematopoietic regeneration and limit aberrant clonal outgrowth in settings of disease.

Public Health Relevance

Blood cell production is the result of distinctive, heterogeneous individual primitive cells collectively generating mature cell offspring. How the process is governed is still poorly understood yet emerging technologies now enable us to examine individual cell behaviors and molecular features. By bringing together a unique group of investigators and their complementary tools and expertise, this program seeks to define the how and why of primitive blood cell behavior under normal and stress conditions. It is intended to create sufficient understanding such that precise interventions can be designed that will shape blood cell production to what is needed for patients under conditions of stress and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL131477-04
Application #
9929628
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Yang, Yu-Chung
Project Start
2017-04-07
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Rodriguez-Fraticelli, Alejo E; Wolock, Samuel L; Weinreb, Caleb S et al. (2018) Clonal analysis of lineage fate in native haematopoiesis. Nature 553:212-216
Gonzalez, David; Luyten, Annouck; Bartholdy, Boris et al. (2017) ZNF143 protein is an important regulator of the myeloid transcription factor C/EBP?. J Biol Chem 292:18924-18936