Strokes in children with Sickle Cell Disease - interplay between bio-mechanical/chemical stimuli

Strokes in children with Sickle Cell Disease:
Dynamic interplay between biomechanical and biochemical stimuli

Manu Platt, Associate Professor, Coulter Department of Biomedical Engineering at Georgia Tech and Emory University

Arterial mechanics are associated with arterial damage, particularly due to remodeling of extracellular matrix, cellular composition, and vasoactivity. This has been examined in other cardiovascular diseases such as atherosclerosis, aging, and stroke. However, sickle cell disease-relevant literature on altered arterial mechanics and their causal link to extracellular matrix remodeling is sparse, particularly in light of the number of arterial complications due to sickle cell disease. Of children born with sickle cell disease, 11% will have a major stroke by age 16, and 30-35% will have a silent stroke impairing cognitive abilities. Later in life, risk for hemorrhagic stroke increases, suggesting an age-related component to arterial damage. Significantly higher velocities measured with transcranial Doppler in cerebral arteries implicates children at risk for strokes with disturbed cerebral hemodynamics. Cathepsins are a family of proteases containing the most potent human elastases and collagenases that we have shown to be upregulated by disturbed blood flow and by inflammatory stimuli, known to be elevated in sickle cell disease. It is unclear, however, how biomechanical and biochemical stimuli integrate to accelerate pathological remodeling of large arteries in these children. We will present our multiscale approach and results demonstrating these links between disturbed blood flow and chronic inflammation due to sickle cell disease, from the cellular level to transgenic animal models up through human computational fluid dynamics to identify new targets to prevent this accelerated artery damage affecting those born with this genetic disease and aging related implications.

Dr. Manu Platt received his B.S. in Biology from Morehouse College in 2001 and his Ph.D. from the Georgia Tech and Emory joint program in biomedical engineering in 2006. He finished his postdoctoral training at MIT in orthopedic tissue engineering and systems biology prior to returning to Georgia Tech and Emory in the joint department of Biomedical Engineering in 2009, where he has since been promoted and tenured. His research centers on proteolytic mechanisms of tissue remodeling during disease progression using both experimental and computational approaches. These diseases of focus are health disparities in the U.S., but global health concerns: pediatric strokes in sickle cell disease, personalized and predictive medicine for breast cancer, and HIV-mediated cardiovascular disease, which has taken him to South Africa and Ethiopia for collaborative work to find solutions for low resource settings. His work has been funded by NIH Director’s New Innovator Award, International AIDS Society, Georgia Cancer Coalition, and the National Science Foundation.

Integrated with his research program are his mentoring goals of changing the look of the next generation of scientists and engineers to include all colors, genders, and backgrounds. Aligned with that goal, Dr. Platt, with Bob Nerem, co-founded and co-directs Project ENGAGES (Engaging the Next Generation At Georgia Tech in Engineering and Science), a program paying African-American high school students from Atlanta Public Schools to be researchers in Georgia Tech labs since 2013. Awards for mentoring and outreach have included the Georgia Tech Diversity Champion award and Georgia Tech Outstanding Doctoral Thesis Advisor. He was named an Emerging Scholar by Diverse: Issues in Higher Education magazine in 2015, the Atlanta 40 under 40 by the Atlanta Business Chronicle in 2016, the Biomedical Engineering Society Diversity Award and Lecture in 2017, and inducted as a Fellow of the American Institute for Medical and Biological Engineering (AIMBE) in 2019, and the Root 100 in 2019.

http://www.platt.gatech.edu