I am a MD/PhD postdoctoral scientist with extensive training in molecular and cell biology from Albert Einstein College of Medicine and Whitehead Institute. My research focuses on the roles of the mDia formin proteins on hematopoietic cells. The mDia formin proteins have well-established roles on the migration of many different cell types. However, their effects on the migration of hematopoietic cells, especially hematopoietic stem cells (HSCs), are poorly understood. With the ideal research environment of Whitehead Institute and excellent mentorship of Dr. Harvey Lodish, I plan to expand my existing scientific and intellectual skills by developing expertise in areas of hematopoeitic stem cells and cell migration, which is vital to my long term career goal of becoming a successful, independent investigator. The goal of my proposed study is to characterize the functional roles of mDia formins, specifically mDia1 and mDia2, on hematopoietic stem cell (HSC) engraftment and migration. HSC engraftment and migration are critical for successful bone marrow transplantation, which has become a routine clinical strategy for treating patients with many blood related diseases such as aplastic anemia, fanconi anemia, sickle cell anemia, beta thalassemia major, leukemia, lymphomas, multiple myeloma, and many immune deficiency disorders. The intracellular signaling pathways regulating HSC engraftment and migration often directly or indirectly target on the actin cytoskeleton network through proteins that regulate polymerization of the actin proteins. The mDia formin proteins are a major actin-nucleating family and their functions in HSCs are poorly understood. To elucidate the roles of mDia formins, specifically mDia1 and mDia2, on HSC migration, genetically modified mouse models and molecular cell biology techniques will be used. Specifically, mouse models deficient of mDia1 or mDia2 will be generated. With these mice, bone marrow and fetal liver Lin-Sca1+Kit+ (LSK) cells, an enriched HSC population, will be purified to perform in vitro migration assays, short-term homing, and long- term engraftment analysis. In collaboration with Drs. Tzutzuy Ramirez Hernandez and Maki Murata-Hori of the Temasek Life Sciences Laboratory in Singapore, the kinetic interactions of mDia1 and mDia2 with actin cytoskeletal proteins and how these interactions regulate hematopoietic stem cell migration will be investigated using confocal fluorescent microscopy and mass spectrometry analysis. In addition, post-translational modifications of mDia1 and mDia2, especially acetylation and phosphorylation, and how these modifications affect their functions in HSC migration will also be characterized.

Public Health Relevance

Current clinical and experimental HSC transplantation is still facing two obstacles: the limited number of transplantable HSCs in a bone marrow or cord blood unit;and a low efficiency of engraftment of transplanted HSCs into recipient bone marrow niches. The project proposed here is directly relevant to these issues. Successful accomplishment of this proposed study will help elucidate how mDia formins mediated regulation of the actin cytoskeleton network affects functions of hematopoietic stem cells. Understanding these processes is highly relevant for bone-marrow transplantation therapies to treat blood-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL102154-03
Application #
8532962
Study Section
Special Emphasis Panel (NSS)
Program Officer
Welniak, Lisbeth A
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$231,475
Indirect Cost
$81,653
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Keerthivasan, Ganesan; Mei, Yang; Zhao, Baobing et al. (2014) Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS. Blood 124:780-90
Zhao, Baobing; Keerthivasan, Ganesan; Mei, Yang et al. (2014) Targeted shRNA screening identified critical roles of pleckstrin-2 in erythropoiesis. Haematologica 99:1157-67
Zhao, Baobing; Mei, Yang; Yang, Jing et al. (2014) Mouse fetal liver culture system to dissect target gene functions at the early and late stages of terminal erythropoiesis. J Vis Exp :e51894