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Site last updated: 05/01/08
Announcements Contact
Two positions are available immediately to develop inhibitors targeting the Notch pathway in T-cell acute lymphocytic leukemia. Successful candidates will join a multidisciplinary team from the Aster, Blacklow, and Pear laboratories investigating T-ALL pathogenesis and inhibition using structural, biochemical, cell culture, and in vivo approaches.
HMS New Research Building
77 Avenue Louis Pasteur, Rm 652
Boston, MA 02115
Lab Phone: (617)525-4417
Fax: (617)525-4414
SCB email:
sblacklow@rics.bwh.harvard.edu
SCB phone: (617)525-4415
Links

Click here to access the Notch Program Project Website

 
The long-term goal of the research program in the Blacklow lab is to combine structural and biochemical studies to understand the molecular logic of cell-surface receptors, focusing on proteins implicated in human disease. Over the next several years, we will continue to explore structure-function relationships in proteins of the vascular and hematopoetic systems, with particular emphasis on members of the lipoprotein receptor and Notch families. The [LDL receptor] is the primary mechanism for uptake of cholesterol-carrying particles into cells. This receptor also serves as a prototype for a large class of related proteins that participate in Wnt signaling and that control cortical migration in development. Mutations in the gene encoding the LDL receptor lead to the genetic disorder familial hypercholesterolemia (FH). FH heterozygotes carry a substantially increased risk for cardiovascular disease. Untreated homozygous FH leads to death at an early age, and is the most compelling evidence supporting the causal link between elevated serum cholesterol levels and atherosclerosis. [LDL receptor-related proteins] control processes as diverse as lipoprotin uptake, clearance of protein complexes from plasma, and and transmission of extracellular singals in development. We are particularly interested in two LDL receptor-related proteins that participate in Wnt signaling and that control cortical migration in developing neurons. [Notch signaling] involves a conserved family of receptors that control a variety of steps in development and differentiation in multicellular animals. Although these receptors are large and complex, all Notch receptors contain a conserved extracellular domain consisting of three "LIN12" modules that are required to maintain the receptors in the resting state prior to ligand-induced activation. We are currently pursuing the structure of the LIN12 domain and its constituent LIN12 modules using solution NMR methods, and studying the detailed role of the LIN12 modules in regulating Notch receptor function. Steve Blacklow, Dr. Blacklow, Dr. Steve C. Blacklow, Stephen C. Blacklow, Notch, LDLR, LDL, MESD, LRP-5, LRP-6, Blacklow lab, LDL-receptor