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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL055321-10A1
Application #
7141486
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
1996-02-01
Project End
2010-04-30
Budget Start
2006-08-15
Budget End
2007-04-30
Support Year
10
Fiscal Year
2006
Total Cost
$420,000
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Gwynn, Babette; Smith, Richard S; Rowe, Lucy B et al. (2006) A mouse TRAPP-related protein is involved in pigmentation. Genomics 88:196-203
Gwynn, Babette; Martina, Jose A; Bonifacino, Juan S et al. (2004) Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex. Blood 104:3181-9
Ciciotte, Steven L; Gwynn, Babette; Moriyama, Kengo et al. (2003) Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1). Blood 101:4402-7
Nguyen, Thuyen; Novak, Edward K; Kermani, Maryam et al. (2002) Melanosome morphologies in murine models of hermansky-pudlak syndrome reflect blocks in organelle development. J Invest Dermatol 119:1156-64
Malik, T H; Shoichet, S A; Latham, P et al. (2001) Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1. EMBO J 20:1715-25
Tse, W T; Tang, J; Jin, O et al. (2001) A new spectrin, beta IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix. J Biol Chem 276:23974-85
Gwynn, B; Ciciotte, S L; Hunter, S J et al. (2000) Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3-independent mechanism. Blood 96:4227-35
Ye, T Z; Gordon, C T; Lai, Y H et al. (2000) Ermap, a gene coding for a novel erythroid specific adhesion/receptor membrane protein. Gene 242:337-45
Azim, A C; Kim, A C; Lutchman, M et al. (1999) cDNA sequence, genomic structure, and expression of the mouse dematin gene (Epb4.9). Mamm Genome 10:1026-9
Gilligan, D M; Lozovatsky, L; Gwynn, B et al. (1999) Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice. Proc Natl Acad Sci U S A 96:10717-22

Showing the most recent 10 out of 22 publications