The proposed Mentored Patient-Oriented Research Career Award is designed to provide the applicant with the didactic training, research skills, and mentored research experience needed to conduct high-quality clinical research on the genetic basis and treatment of inherited diseases. The didactic component will lead to an MS degree in Clinical Research in the K30 Clinical Research Curriculum offered at Mount Sinai. The mentored research focuses on Type 1 Gaucher disease (GD), the most common lysosomal storage disease, which is especially prevalent in individuals of Ashkenazi Jewish (AJ) descent. The deficient activity of acid Beta-glucosidase, encoded by mutations in its gene (GBA), results in the accumulation of glucosylceramide (GL-1), particularly in the macrophage-monocyte system. The disease phenotype has marked variability in patients with the N370S/N370S genotype (i.e., N370S homozygotes), ranging from severe hepatosplenomegaly, pancytopenia, and debilitating bone disease in childhood to overtly asymptomatic in late adulthood. Significant phenotypic diversity is also seen in N370S/""""""""null"""""""" (N370S/84GG or N370S/IVS2 +1) patients. The proposed research will investigate the hypothesis that modifier genes are responsible for the markedly different phenotypes in AJ N370S homozygotes and N370S/null patients.
The specific aims i nclude: 1) characterizing and comparing the phenotypes in asymptomatic and symptomatic AJ N370S homozygotes, and mild and severe N370S/""""""""null"""""""" patients, 2) identifying genes using microarrays that are markedly differentially expressed in blood monocytes isolated by fluorescence-activated cell sorting (FACS) from symptomatic and severe N370S homozygotes and normal controls, 3) identifying/investigating candidate modifier genes, including two involved in GL-1 metabolism, as well as selected genes adjacent to and in linkage disequilibrium (LD) with GBA, for polymorphisms that correlate with phenotype. These studies should provide insight into modifier genes responsible for the marked phenotypic differences in N370S homozygotes. In addition, the proposed studies will provide the applicant with the skills and experience necessary to conduct independent, high-quality patient-oriented research. The applicant will have protected research time, dedicated laboratory space, and access to the General Clinical Research Center (GCRC) and core facilities. Her development will be fostered by the commitment of her Co-Mentors to guide her in the proposed studies and in the responsible conduct of research, and by the outstanding research and intellectual environment at Mount Sinai.
