The University of Texas Health Science Center at Houston
McGovern Medical School
Institute of Molecular Medicine
With an unprecedented longer life expectancy, our society is facing a pressing challenge from aging-related neurodegenerative disorders (NDs) such as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases. To understand the pathogeneses of these devastating brain disorders, we need to address two essential questions: (1) What are the normal functions of disease-causative genes? (2) How are the formation of protein aggregates, a common pathological hallmark of NDs, regulated? Our laboratory employs Drosophila, commonly known as the fruit fly, which is one of the best-studied model organisms, to address these questions, with focus on the following areas:
I. Dissecting the endogenous function of the Huntington’s disease gene Huntingtin: HD is caused by an abnormal expansion of a polyglutamine tract in the Huntingtin (Htt) protein, and disruption of its normal functions has been implicated in the disease pathogenesis. To elucidate its still mysterious endogenous functions, we have knocked out the gene in the fruit fly that is homologous to human Htt and found that this Drosophila Htt (dhtt) affects the mobility and long-term survival of adult animals as well as axonal terminal complexity in the brain. We are currently taking advantage of the abundant experimental tools available in Drosophila to dissect out the normal function of this enigmatic protein.
II. Studying the formation of intracellular protein aggregates: Formation of protein aggregates is believed to be a dynamic process involving multiple intermediate species of different sizes and conformations (e.g., oligomers, proto- and pre-fibrils, fibrils), and their effects on neuronal degeneration may vary from toxic to protective. Thus, understanding their regulation will be important in finding effective treatments for these diseases. We have established a cell-based quantitative high-throughput assay that allows automated measurement of aggregates within Drosophila cells and have further carried out a genome-wide RNA interference (RNAi) screen on mutant Htt protein, from which we identified a diverse group of regulators that affected aggregates formation. Using this established high-throughput assay and the isolated regulators as entry points, we are systematically studying the molecular networks regulating aggregates formation and neuronal toxicity.
III. Analyzing the intracellular handling of neurotransmitter dopamine in dopaminergic neurons: PD is characterized by the progressive loss of dopaminergic (DA) neurons in the brain. To facilitate the study of PD using the fly, we are developing in vivo assays for analyses of intracellular handling of dopamine in Drosophila tissues.
Tutorials in our laboratory will expose the students to multi-disciplinary approaches for studying the pathogenic mechanisms underlying human NDs, including neuroscience analyses, high-resolution imaging, genome-wide assays, as well as traditional cell biology, biochemistry and many genetic manipulation tools in the classical fruit fly model system.
Education & Training
Ph.D. - Yale University - 2001