Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemias. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a hematopoietic model has only recently been appreciated. The mechanisms that maintain blood stem cells in Drosophila show remarkable conservation in strategy of development and function with mammalian systems. The proposed work intends to determine the molecular pathways that maintain stem cell homeostasis. Also proposed is the role of systemic signals and nutrient deprivation on myeloid cell development. These are developmentally and medically relevant problems for which model systems amenable to genetic screens are essential to develop. The proposal has four specific aims.
In Aim 1, a homeostatic model by which blood precursors are maintained not only by a signal from a niche, but also from the cells that have started differentiating will be developed.
In Aim 2, the involvement of the transcription factor STAT in the maintenance of stem cell fate in Drosophila will be investigated.
In Aim 3, the role of extracellular matrix components that control the integrity of stem cells will be studied. In the final aim, signals arising from the brain that control blood stem cell maintenance in Drosophila will be investigated and their role in starvation induced stem cell loss studied.

Public Health Relevance

The genetic basis of blood development and disorders are extremely important to understand in order to make progress on understanding immune challenges and leukemias. The fruit fly, Drosophila is a model organism in which such studies can be achieved with great predictive power for the human condition. This proposal seeks to understand the molecular mechanisms by which blood stem cells are maintained, and also how these cells respond to stresses that result from starvation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067395-11
Application #
8286224
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Thomas, John
Project Start
2001-05-10
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$135,000
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Evans, Cory J; Liu, Ting; Banerjee, Utpal (2014) Drosophila hematopoiesis: Markers and methods for molecular genetic analysis. Methods 68:242-51
Mondal, Bama Charan; Shim, Jiwon; Evans, Cory J et al. (2014) Pvr expression regulators in equilibrium signal control and maintenance of Drosophila blood progenitors. Elife 3:e03626
Shim, Jiwon; Mukherjee, Tina; Mondal, Bama Charan et al. (2013) Olfactory control of blood progenitor maintenance. Cell 155:1141-53
Grigorian, Melina; Liu, Ting; Banerjee, Utpal et al. (2013) The proteoglycan Trol controls the architecture of the extracellular matrix and balances proliferation and differentiation of blood progenitors in the Drosophila lymph gland. Dev Biol 384:301-12
Shim, Jiwon; Mukherjee, Tina; Banerjee, Utpal (2012) Direct sensing of systemic and nutritional signals by haematopoietic progenitors in Drosophila. Nat Cell Biol 14:394-400
Sinenko, Sergey A; Shim, Jiwon; Banerjee, Utpal (2012) Oxidative stress in the haematopoietic niche regulates the cellular immune response in Drosophila. EMBO Rep 13:83-9
Mukherjee, Tina; Kim, William Sang; Mandal, Lolitika et al. (2011) Interaction between Notch and Hif-alpha in development and survival of Drosophila blood cells. Science 332:1210-3
Mondal, Bama Charan; Mukherjee, Tina; Mandal, Lolitika et al. (2011) Interaction between differentiating cell- and niche-derived signals in hematopoietic progenitor maintenance. Cell 147:1589-600
Yavari, Amir; Nagaraj, Raghavendra; Owusu-Ansah, Edward et al. (2010) Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell 19:54-65
Sinenko, Sergey A; Hung, Tony; Moroz, Tatiana et al. (2010) Genetic manipulation of AML1-ETO-induced expansion of hematopoietic precursors in a Drosophila model. Blood 116:4612-20

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