果冻影院

Dr. Dahms received her Bachelor of Science degree from Marquette University in 1980 and her Doctorate degree in Biochemistry from the Johns Hopkins University School of Medicine in 1986. She was a postdoctoral fellow at Washington University School of Medicine from 1986-1989 where she isolated and characterized the cDNA clones for the receptors involved in targeting lysosomal enzymes to the lysosome. She joined the faculty of the 果冻影院 in 1989.

Lysosomes carry out catabolism critical to many processes, including the disposal of abnormal proteins, cell survival, antigen processing, and inactivation of pathogenic organisms. Receptors deliver hydrolytic enzymes to lysosomes to generate functional lysosomes. Lysosomal storage diseases (LSDs) are caused by mutations in lysosomal proteins, mainly enzymes, that result in defective catabolism and substrate accumulation (‘storage’) of undegraded material within lysosomes, with lysosomal and cellular dysfunction leading to cell death and a shortened life span. As a group LSDs are among the most common genetic disorders in children, and their progressive and debilitating nature is due to their impact on multiple organ systems. Treatment is symptomatic for most LSDs, with only 11 out of the ~70 LSDs having FDA-approved therapies. Our goal is to define the molecular mechanism of receptor-mediated delivery of lysosomal enzymes to lysosomes, and thereby identify new strategies for the treatment of LSDs and other human diseases dependent upon lysosomal function.

Receptor Structural Biology & Protein-Carbohydrate Interactions

Two mannose 6-phosphate receptors (MPR), the cation-independent (CI-MPR) and the cation-dependent MPR (CD-MPR), bind a unique carbohydrate determinant, mannose 6-phosphate (M6P), on lysosomal enzymes’ N-glycans to mediate their delivery to lysosomes. CI-MPR, with its large extracellular region comprised of 15 contiguous domains, is the primary receptor responsible for lysosomal enzyme trafficking and CI-MPR forms the basis of enzyme replacement therapy used in the treatment of several LSDs. We have defined the glycan binding properties of the MPRs using biochemical, structural, cellular, and in vivo approaches. Our collaborative studies with Drs. Jung-Ja Kim and Brian Volkman using X-ray crystallography and NMR spectroscopy have provided the first and only three-dimensional structures reported to date of the carbohydrate binding sites of the MPRs.

Pathogenesis of lysosomal storage diseases (Fabry disease)

We are investigating the mechanisms underlying the diverse clinical symptoms experienced by patients with LSDs. Fabry disease, the most common LSD, is caused by a deficiency of the lysosomal enzyme, α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. We generated a rat model of Fabry disease, the first non-mouse model. Unlike Fabry mouse models, we show that Fabry rats recapitulate ocular, hearing, kidney, heart, and pain phenotypes experienced by Fabry patients and can be used to study disease mechanisms and test therapies.

Regulation of cell growth, survival, and differentiation

We are interested in the molecular mechanisms that regulate cell growth and differentiation. Our studies have focused on the role of growth factors (IGF2), proteases (plasminogen), and receptors (uPAR) in modulating cellular growth and differentiation of mammalian cells. The multifunctional CI-MPR (also known as IGF2R) also regulates the bioavailability of circulating IGF2 by targeting it to the lysosome, and in several animal models functions as a tumor suppressor of IGF2-dependent tumors. We have shown that the CI-MPR regulates fibroblast to myofibroblast differentiation and is critical for pancreatic beta cell survival.