Pathogenesis in sickle cell diseases results from polymerization of deoxyhemoglobin S and the resultant rigid gel. The purpose of this collaborative and multidisciplinary program is to identify interaction sites responsible for different levels of structure and associated pathophysiology and then to characterize the interactions. The hierarchy of structure consists of the basic double strand of hemoglobin molecules, the fiber composed of seven double strands, the gel network, and the gel domain and, in vivo, effects of the red cell. The investigators will connect specific sites and interactions and then rate this information to the equilibrium and kinetic properties that control pathophysiology. The basic methods are (1) identification of specific sites, to be achieved, with recombinant hemoglobin mutants; (2) techniques to observed (DIC) microscopy, and combination of light based methods including absorption, scattering and birefringence; and (3) physical chemical methods to characterize equilibria and kinetics. Specific studies will examine (a) the sites of heterogeneous nucleation, the reaction that is the cause of the rapid, exponential, progress of gelatin; (b) sites of interfiber cross-linking that produce the gel network and solid-like rheology; c) structure and mechanisms of assembly of domain; (d) effects of the red cell membrane and the red cell contents of gelation; (e) effects of the tertiary structure of hemoglobin, Finally, (f) intrafiber interactions will be examined to identify sites critical for polymer structure and assembly and for characterization and energetics of the interactions. Identification of sites and characterization of interactions would further the development of treatments for sickle cell disease in two ways: A rational design of site-specific agents that bind to hemoglobin and inhibit gelation would be facilitated. Conditions that promote or inhibit gelation in vivo could be identified and related to the natural history of the disease and prophylactic measures against sickle crises.
|Effective start/end date||8/6/97 → 12/31/08|
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.