Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder of organelle biogenesis that affects lysosomes and the lysosome-related organelles (LROs), melanosomes and platelet dense bodies, leading to lysosomal storage disease/lung fibrosis, oculocutaneous albinism and prolonged bleeding. In both mice and human beings, HPS is genetically heterogeneous. The overall goal of this research is to identify genes critical to the development and function of the LROs and to define their roles in the etiology and pathology of HPS. Specifically, we test the hypothesis that defects in novel gene products perturb organelle biogenesis and result in HPS.
The specific aims are to: (1) positionally clone the gene defects underlying three novel mouse models of HPS generated by chemical mutagenesis, characterize their protein products and screen for corresponding defects in human HPS patients using existing fibroblast cell panels; (2) identify the role of R26w/Trappc6b in organelle biogenesis/HPS by generating and phenotyping platelet- and melanocyte-specific conditional knockout mice; and (3) implement a mutagenesis strategy (dominant enhancer/suppressor screen) to identify genetic modifiers/interacting loci that influence the mouse HPS phenotype. Ultimately, these studies will (a) identify candidate genes for human HPS; (b) provide entry points into novel pathways critical to organelle biogenesis, a fundamental process in cell biology relevant to all cell types; and (c) provide potential targets for diagnostic and therapeutic interventions for HPS and related disorders of vesicular trafficking. Relevance to Public Health Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by loss of pigment in the skin and eyes (albinism), prolonged bleeding, and lung fibrosis. Lung fibrosis typically leads to death in the 4th to 5th decades. This study is designed to identify the underlying genetic causes of HPS, which will provide avenues of research for potential therapies. ? ? ?
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