Cardiovascular research in the last decade has definitively shown that the hormone aldosterone has pro- inflammatory vascular effects, including biophysical changes in endothelial cells such as: increased cell stiffness, increased cell volume, increased surface adhesion molecule expression, and decreased nitric oxide production, among others. What has not been studied, however, is how these aldosterone-induced alterations in endothelial cell mechanical properties affect sickle cell vaso-occlusion, which is also a biophysical phenomenon, and how aldosterone may also alter the biophysical properties of blood cells. We hypothesize that aldosterone-mediated cell mechanical effects influence sickle cell vaso-occlusion and propose to use single-cell mechanical techniques that we have previously developed in combination with conventional assays to explore how aldosterone affects microvascular occlusion. Specifically, we will determine and investigate the underlying mechanisms of aldosterone's effect on endothelial adhesion to sickle red cells and leukocytes (Aim 1), sickle red cell and leukocyte deformability (Aim 2), and cell aggregation and microcirculatory flow in a three-dimensional in vitro model of the microvasculature (Aim 3). The candidate has chosen a novel training and career path and has recently completed a fellowship in pediatric hematology/oncology combined with a PhD in bioengineering. This K08 grant will allow Dr. Lam to receive all the necessary training to develop into a new breed of independent researcher in academic medicine: a physician-scientist-engineer who applies bioengineering and nanoscience techniques to develop new biomedical devices for diagnosis and study of pediatric blood diseases. Specifically, this award will be used to further his training in vascular biology, the cell biology of adhesion, and advanced microfabrication and microfluidics to develop complex lab-on-chip devices for sickle cell disease. This research will be conducted in a unique bioengineering lab at UC Berkeley that focuses on applying and developing new optical microscopy, force microscopy, and microfluidic techniques to study cell mechanics in health and disease, with close clinical connections at UC San Francisco.
By investigating whether the hormone aldosterone plays a role in sickle cell anemia, this work will improve our understanding of- and new treatments for-this complex and incurable disease. In addition, the devices we develop for this project will serve as prototypes for new diagnostic and drug discovery tools for this debilitating and potentially fatal disease that affects the lives of tens of thousands of Americans every day.
|Tran, Reginald; Ahn, Byungwook; Myers, David R et al. (2014) Simplified prototyping of perfusable polystyrene microfluidics. Biomicrofluidics 8:046501|
|Brown, Ashley C; Stabenfeldt, Sarah E; Ahn, Byungwook et al. (2014) Ultrasoft microgels displaying emergent platelet-like behaviours. Nat Mater 13:1108-1114|
|Ciciliano, Jordan C; Tran, Reginald; Sakurai, Yumiko et al. (2014) The platelet and the biophysical microenvironment: lessons from cellular mechanics. Thromb Res 133:532-7|
|Myers, David R; Sakurai, Yumiko; Tran, Reginald et al. (2012) Endothelialized microfluidics for studying microvascular interactions in hematologic diseases. J Vis Exp :|
|Tsai, Michelle; Kita, Ashley; Leach, Joseph et al. (2012) In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology. J Clin Invest 122:408-18|
|Kita, Ashley; Sakurai, Yumiko; Myers, David R et al. (2011) Microenvironmental geometry guides platelet adhesion and spreading: a quantitative analysis at the single cell level. PLoS One 6:e26437|
|Lam, Wilbur A; Chaudhuri, Ovijit; Crow, Ailey et al. (2011) Mechanics and contraction dynamics of single platelets and implications for clot stiffening. Nat Mater 10:61-6|