The Emory Center of Excellence in Hemoglobinopathy Research (CEHR) aspires to improve the health of individuals with sickle cell disease (SCD) by developing novel therapeutics and biomarkers for the major cause of death in SCD acute chest syndrome (ACS), through the discovery of critical molecular and cellular mechanisms, and genetic markers of human diversity that influence ACS, and to build capacity in our community in translational research, awareness and career pipelines in biomedical research. Our overarching scientific hypothesis is that heme, a product of tissue damage and hemolysis induces ACS via interaction with toll-like receptor 4 (TLR4). The Emory CEHR assembles a multi-disciplinary team of geneticists, hematology physicians and scientists, and lung biologists to rigorously test this hypothesis and explore its therapeutic potential in three inter-related Specific Aims: [1] Define cellular and molecular mechanisms, and inhibitors of heme-induced endothelial dysfunction and lung injury. [2] Determine the role of TLR4 in the development of ACS in SCD mice and generate pre-clinical data for novel therapeutics. [3] Identify genetic polymorphisms associated with the incidence and severity of ACS. A Translational Research Skills Development Core aims to train an MD and a PhD scientist in clinical research and provide mentored research experience for them to become independent investigators. Training for the MD scholar will emphasize phase I clinical trial design, execution and analysis, and the scholar will participate in the design of a Phase I trial of candidate drug(s) emerging from the research project. The PhD scholar, pursuing training in clinical research and genomics, will also be positioned to participate in the research studies of the CEHR. The Sickle Cell Summer Research Training Program for high school students links with a robust program of career development for minority students at Morehouse School of Medicine. In summary, the proposed project of the Emory CEHR will rigorously test a novel mechanism of lung injury, identify candidate drugs that interfere with it, and lay a solid foundation - in both scientific and human resources - for the development of an entirely new therapeutic approach to preventing or treating ACS in sickle cell disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL117721-01
Application #
8468275
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Goldsmith, Jonathan C
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2013-08-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,897,529
Indirect Cost
$580,450
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Carden, Marcus A; Fay, Meredith E; Lu, Xinran et al. (2017) Extracellular fluid tonicity impacts sickle red blood cell deformability and adhesion. Blood 130:2654-2663
Mannino, Robert G; Santiago-Miranda, Adriana N; Pradhan, Pallab et al. (2017) 3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro. Lab Chip 17:407-414
Myers, David R; Qiu, Yongzhi; Fay, Meredith E et al. (2017) Single-platelet nanomechanics measured by high-throughput cytometry. Nat Mater 16:230-235
Chaturvedi, Shruti; Bhatnagar, Pallav; Bean, Christopher J et al. (2017) Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia. Blood 130:686-688
Walker, Aisha L; Ofori-Acquah, Solomon F (2017) Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced ?-globin expression in erythroid progenitors. Exp Hematol 45:69-73.e2
Owusu-Ansah, Amma; Ihunnah, Chibueze A; Walker, Aisha L et al. (2016) Inflammatory targets of therapy in sickle cell disease. Transl Res 167:281-97
Ghosh, Samit; Ihunnah, Chibueze A; Hazra, Rimi et al. (2016) Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice. JCI Insight 1:
Tan, Fang; Ghosh, Samit; Mosunjac, Mario et al. (2016) Original Research: Diametric effects of hypoxia on pathophysiology of sickle cell disease in a murine model. Exp Biol Med (Maywood) 241:766-71
Charrin, Emmanuelle; Ofori-Acquah, Solomon Fiifi; Nader, Elie et al. (2016) Inflammatory and oxidative stress phenotypes in transgenic sickle cell mice. Blood Cells Mol Dis 62:13-21
Mannino, Robert G; Myers, David R; Ahn, Byungwook et al. (2015) ""Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions"". Sci Rep 5:12401

Showing the most recent 10 out of 15 publications