Room 328, Clinical Research Building
Philadelphia, PA 19104-6148
The Hebrew University, Jerusalem, Israel, 1973.
Tel Aviv University, Tel Aviv, Israel, 1975.
Ph.D. (Biological Chemistry)
Harvard University, 1978.
Description of Research ExpertiseResearch Interests
-The Survival of Motor Neurons (SMN) complex
-Spinal Muscular Atrophy/neurogenerative disease
-Assembly and transport of RNA-protein (RNP) complexes
-High throughput screening.
Key words: RNA, RNPs (ribonucleoproteins), SMN, Spinal Muscular Atrophy, High throughput screening, neurodegneration, nuclear transport.
Description of Research
The functional forms of RNAs in cells are ribonucleoprotein (RNP) complexes, the complexes that contain RNAs and their associated RNA-binding proteins. The RNP proteins profoundly influence every aspect of the biogenesis and function of the RNAs, including their processing, transport, localization, interactions, translation, and stability. We have been particularly interested in RNA-binding proteins and the complexes they form with pre-mRNAs (hnRNAs) and mRNAs. We identified and characterized the major proteins that interact with these RNAs (hnRNPs and mRNPs) and studied them in detail. These studies led to the identification of RNA-binding domains, novel nuclear structures and transport pathways, and opened up new areas of research on important human genetic diseases, including spinal muscular atrophy (SMA) and fragile X syndrome. Over the past several years we have been involved in the discovery of a complex of proteins that forms on mRNAs in the wake of the splicing of pre-mRNAs at the site of exon ligation. This complex, the exon-junction complex (EJC), is comprised of several proteins, (including Y14, mago, RNP S1, Upf3, ALY, Srm160, eIF4A3) some of which remain associated with the mRNA after it is exported from the nucleus to the cytoplam. The EJC proteins play important roles in the export of mRNAs as well as in their translation and localization, and they serve as a marker that allows cells to define the authentic termination codon and thus detect and destroy mRNAs that contain pre-mature termination codons (nonsense-mediated decay).
We are now particularly interested in a large multi-protein complex, the Survival of Motor Neurons Protein (SMN) complex, that we described over the last few years. The SMN compex functions as an assembly machine for spliceosomal small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs, in pre-mRNA splicing, and in the assembly of mRNA factories (transcriptosomes). The discovery of this kind of activity was unexpected because several RNPs have been known to have the capacity to self-assemble from purified components in vitro. In cells, however, such assembly processes would probably be inefficient and prone to inaccuracies without the assistance of the SMN complex. It casts a new light on how RNA-protein interactions, the key to post-transcriptional gene expression, are orchestrated. Some of our main objectives are to determine the complete composition, interactions, structure, and functions of the SMN complex. To assemble RNPs, the SMN complex must recognize and bring together their protein and RNA components. We are engaged in determining the specific features in the RNAs and the proteins that mediate their binding to the SMN complex. SMN is essential for viability of all cells, but reduced levels of this protein cause Spinal Muscular Atrophy (SMA), a common motor neuron degenerative disease. From studies of the SMN complex emerge new approaches for discovering potential therapeutics for SMA that we are currently pursuing.
Another major current effort is the use of lab automation and robotics for high-throughput screening (HTS) of libraries of small molecules in search of potential therapeutics for SMA. In particular, using cell-based assays we developed, we are searching for compounds that may alleviate the deficiency in the SMN protein and increase the amount of functional SMN protein in cells, as well as for compounds that may improve the survival of cells at low SMN. We have identified promising leads and are studying them further. We are also using HTS as a general approach for discovery of biologically active small molecule effectors of several pathways that we are interested in.
Please visit the lab to discuss available projects.
Jennifer Bachorik, Ph.D. - Research Associate
Mike Berg, Ph.D. - Research Associate
E. Anna Bridges - Lab Manager
Sungchan Cho, Ph.D. - Postdoctoral Fellow
Kazuhiro Fukumura, Ph.D. - Postdoctoral Fellow
Tina Glisovic, Ph.D. - Research Associate
Jennifer Jackson - Administrative Assistant
Daisuke Kaida, Ph.D. - Postdoctoral Research Fellow
Mumtaz Kasim, Ph.D. - Research Associate
Isabela Oliva, Ph.D. - Research Specialist
Anna Maria Pinto, M.D. - Postdoctoral Research Fellow
Ria Sotiriou, Ph.D. - Postdoctoral Research Fellow
Lili Wan, Ph.D. - Research Associate
Congli Wang, Ph.D. - Research Specialist
Jeongsik Yong, Ph.D. - Research Associate
Ihab Younis, Ph.D. - Research Associate
Zhenxi Zhang, Ph.D. - Research Associate
Rundong Zhang, Ph.D. - Research Specialist