Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemia. 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. This study utilizes powerful genetic tools and reagents available for the Drosophila model system to understand how local and global signals affect blood cell development. In particular, we will analyze blood cell differentiation within the fruit fly blood-producing organ to assess how cell cycle, cell differentiation, and organ morphology are influenced during normal development as well as in the presence of stressful environmental stimuli. This proposal consists of three major aims.
Aim 1 describes experiments aimed at mapping the organismal connection between defects in CO2 reception and blood cell maturation.
In Aim 2 we propose to fully characterize the cell cycle profile of blood progenitors and we will uncover the signaling pathways regulating proteins controlling cell cycle progression. Finally, in Aim 3, we will identify and characterize te effects of tumor growth in epithelial tissue on blood cell development in the mesoderm derived hematopoietic organ. The role of tumor burden on the blood/immune system is of great importance to human cancer and injury, and Drosophila provides an ideal model for understanding the mechanisms in detail. Overall, the research we propose will lead to critical insights into how blood cells are influenced by external and internal stimuli, the mechanisms of which are likely to be conserved in humans. The PI will be involved in mentoring and supervision of the work that will involve the training of 4 postdoctoral fellows and 1 graduate student. Additionally, the laboratory traditionally trains a large number of undergraduates in research. The typical undergraduate spends 2-3 years in the laboratory; postdocs, 5 years and graduate students 5-6 years. The main scientific disciplines our research encompasses include developmental biology and genetics. All graduate and postdoctoral researchers involved are extremely knowledgeable in these two fields, and the more experienced members of the lab will pass along this familiarity to newer members.

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 leukemia. 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 local and systemic molecular mechanisms underlying control of blood cell proliferation and differentiation and how environmental stimuli (including CO2 reception and tumor burden) influence this regulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067395-16
Application #
9415427
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Thomas, John
Project Start
2001-05-10
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
16
Fiscal Year
2018
Total Cost
Indirect Cost
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
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
Evans, Cory J; Liu, Ting; Banerjee, Utpal (2014) Drosophila hematopoiesis: Markers and methods for molecular genetic analysis. Methods 68:242-51
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
Honti, Viktor; Cinege, Gyöngyi; Csordás, Gábor et al. (2013) Variation of NimC1 expression in Drosophila stocks and transgenic strains. Fly (Austin) 7:263-6
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
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
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
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
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

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