The candidate is a clinical fellow in pathology proposing a 5-year development plan for a career in academic clinical laboratory medicine. The candidate has training and professional experience in clinical pathology, applied mathematics, and computer science. He will be mentored and advised by both H. Franklin Bunn, M.D., Professor of Medicine at Harvard Medical School, and by Lakshminarayanan Mahadevan, Ph.D., Professor of Applied Mathematics at Harvard University and of Systems Biology at Harvard Medical School. Dr. Bunn is an expert in the field of red blood cell biology and pathophysiology. Professor Mahadevan is an expert in the field of biophysical modeling. The candidate's advisory team includes Sangeeta Bhatia, M.D., Ph.D., Associate Professor of Health Sciences and Technology at MIT, Carlo Brugnara, M.D., Professor of Pathology at Harvard Medical School, David Dorfman, M.D., Ph.D., Associate Professor of Pathology at Harvard Medical School, and William Eaton, M.D., Ph.D., Chief of Chemical Physics, NIH. This career development program will promote his further acquisition of the theoretical and practical skills necessary to model and understand disorders of blood flow and to translate those findings to the clinical laboratory or the bedside. The research project will investigate the causes of vaso-occlusion in sickle cell disease. Vaso-occlusion is a process occurring at multiple levels of scale: nanoscopic hemoglobin polymerization, microscopic cellular sickling and endothelial response, and macroscopic vessel occlusion. Control parameters for vaso-occlusion include hemoglobin S concentration, oxygen tension, hematocrit, endothelial phenotype, vessel diameter, and pressure gradient. This dynamic pathophysiologic process will be studied using microfluidic devices and computational image analysis. Preliminary work has demonstrated the ability to evoke, reverse, perturb, and inhibit the occlusion of sickle cell blood in a limited artificial microfluidic environment. The proposed work will explore the process of vaso-occlusion, its response to perturbation, and its correlation with patient symptom severity by (1) characterizing the dynamics of occlusion in an existing limited microfluidic device under a range of control parameter values, (2) expanding the range of initial conditions, parameter values, and blood specimen manipulations, and (3) enhancing the experimental device with adhesion molecules, complex geometries, and the introduction of small molecules. This work will advance our understanding of the mechanism of this disease process and has potentially immediate applications for translation to the clinical laboratory for monitoring and treatment stratification of sickle cell patients. This work may also serve as a test bench for the optimization of existing treatment regimens and the identification of altogether novel therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (M1))
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Bishop, Terry Rogers
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Massachusetts General Hospital
United States
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Patel, Harsh H; Patel, Hasmukh R; Higgins, John M (2015) Modulation of red blood cell population dynamics is a fundamental homeostatic response to disease. Am J Hematol 90:422-8
Golub, Mari S; Hogrefe, Casey E; Malka, Roy et al. (2014) Developmental plasticity of red blood cell homeostasis. Am J Hematol 89:459-66
Byun, HeeSu; Hillman, Timothy R; Higgins, John M et al. (2012) Optical measurement of biomechanical properties of individual erythrocytes from a sickle cell patient. Acta Biomater 8:4130-8
Wood, David K; Soriano, Alicia; Mahadevan, L et al. (2012) A biophysical indicator of vaso-occlusive risk in sickle cell disease. Sci Transl Med 4:123ra26
Kim, Youngchan; Higgins, John M; Dasari, Ramachandra R et al. (2012) Anisotropic light scattering of individual sickle red blood cells. J Biomed Opt 17:040501
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Higgins, John M; Mahadevan, L (2010) Physiological and pathological population dynamics of circulating human red blood cells. Proc Natl Acad Sci U S A 107:20587-92