Dr. Wei Li's Laboratory
Beijing Children's Hospital, Capital Medical University


1. Lysosomal Trafficking in LRO Biogenesis and Signal Transduction

Hermansky-Pudlak syndrome (HPS) is a heterogeneous recessive disorder characterized by oculocutaneous albinism, bleeding tendency and ceroid deposition by affecting the biogenesis of multiple lysosome-related organelles (LROs) such as melanosomes, platelet dense granules (see a review of HPS by Wei and Li. Pigment Cell Melanoma Res, 2013). In Dr. Richard T. Swank's laboratory, at least 16 mouse Hermansky-Pudlak syndrome (HPS) mutants have been described (reviewed by Swank, et al. Pigment Cell Res, 1998). Through positional candidate cloning, the first human HPS gene, HPS1, was identified in 1996. This prompted the identification of the first murine HPS gene, Hps1/ep, in 1997 and the cloning of other 15 HPS genes in mouse or human thereafter (reviewed by Li, et al. BioEssays, 2004). Data integration of all these HPS genes is deposited in the Hermansky-Pudlak Syndrome Database (Li, et al. Hum Mutat, 2006).

Currently, the 16 cloned HPS genes fall into several HPS associated complexes (HPACs) involved in lysosomal trafficking. These HPACs include AP-3, HOPS, BLOC-1, BLOC-2, BLOC-3, Rab GGTase II, Rab38 (summarized by Wei and Li. Pigment Cell Melanoma Res, 2013). Lysosomal trafficking is involved in regulating the biogenesis of lysosomes together with very specialized lysosome-related organelles (LROs) such as platelet dense granules, melanosomes, Weibel-Palade bodies, MHC II compartments, lytic granules, and synaptic vesicles. In addition, it has been known that signal transduction is modulated by lysosomal degradation of signals. Disruption of lysosomal trafficking could lead to the defects of LROs and disrupted signal transduction, which leads to a variety of diseases such as albinism, metabolic disorders, neurodegeneration, schizophrenia, developmental defects, cancer.

Our short-term and long-term research goals are to:

(1) Define the unknown components or interactions existing in the HPACs to build up the network in lysosomal trafficking.

(2) Dissect the cargo-specific lysosomal trafficking mechanisms mediated by the HPACs.

(3) Define the biogenesis and the physiological roles of the specialized LROs, such as melanosomes, platelet dense granules, synaptic vesicles, Weibel-Palade bodies.

2. Translational Studies of Trafficking Jams

As the mutations of the HPS genes lead to traffic jams causing albinism, neurodegeneration, schizophrenia and immunodeficiency, the translation of our research to clinical applications is to

(1) Provide an optimized genetic testing strategy in albinism and other inherited diseases.

(2) Provide genetic counseling for these devastating diseases through our online genetic counseling network (CGCN).

(3) Search for new drug targets.

(4) Identify novel disease-causative genes.