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ZAMORE LABORATORY

 

OUR RESEARCH

 
We are passionately committed to understanding how small RNAs, small interfering RNAs (siRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs), regulate gene expression in plants, fungi, and animals.
 
The model organism Drosophila melanogaster is the center of our studies, but what we learn in flies, we test in mammalian cell extracts, in cultured human and mouse cell lines, and in vivo in mice to identify where these processes are conserved and where they diverge between flies and mammals.
 

piRNAs and endo-siRNAs: defending the genome. 

piRNAs form the third major class of small RNAs in flies and mammals. The dominant class of piRNAs in flies silence selfish genetic elements such as transposons. piRNAs are produced by a mechanism distinct from both the RNAi and miRNA pathways. Understanding how piRNAs are made and how they function is a major focus in the laboratory. We also seek to understand the endo-siRNA pathway, which defends the soma against selfish genetic elements, much as the piRNA protects the germline.

miRNA biogenesis and function.

miRNAs are small RNAs that regulate mRNA expression. miRNAs nearly always pair partially with their target mRNAs, unlike siRNAs which typically pair fully. In flies, siRNAs are made by Dicer-2, but miRNAs are produced by Dicer-1, acting together with its partner protein, Loquacious (Loqs). Loqs is required for germline stem cells to retain their identity, and a major effort in our laboratory is to identify how Loqs helps specify stem cell fate. The structure of a small RNA duplex, not the identity of the Dicer paralog that produces them, determines its sorting between two different Argonaute proteins, Ago1 and Ago2, that regulate mRNA expression by distinct mechanisms. While we have learned much about the molecular basis for partitioning highly paired small RNA duplexes into the Ago2 pathway, we know little about the parallel mechanism that sends most, but not all, miRNAs to Ago1. We are actively seeking to identify the Ago1-loading machinery and to learn if such small RNA sorting occur in mammals.

 

The mechanism of RNA interference (RNAi).  

A decade of study of the RNAi pathway in our and other laboratories has established a mechanistic framework for RNAi in flies, but many challenges remain. New technologies are under development in our laboratory to meet these challenges, including single-molecule fluorescence techniques to study the cycle of RISC maturation and function, and deep sequencing methods that allow us to compare millions of different sequences in a single experiment to test the contribution of each siRNA nucleotide to binding and catalysis. Many of the proteins required for RNAi in Drosophila have subsequently been identified as components of the human pathway, but we do not yet know how they function. Building a better understanding of the human RNAi pathway is a key challenge for our laboratory.

 

 

PRINCIPAL INVESTIGATOR

Phillip D. Zamore, Ph.D.

Chair, RNA Therapeutics Institute

Investigator, Howard Hughes Medical Institute

Professor, Biochemistry & Molecular Pharmacology

Gretchen Stone Cook Professor of Biomedical Sciences

 

Phillip D. Zamore, Ph.D. has been an Investigator of the Howard Hughes Medical Institute since 2008. He is the Chair of the RNA Therapeutics Institute, which was established at the University of Massachusetts Medical School in 2009. Dr. Zamore also is Professor of Biochemistry and Molecular Pharmacology, the department he joined in 1999, and he became the Gretchen Stone Cook Professor of Biomedical Sciences in 2005.

 

Dr. Zamore received his A.B. (1986) and Ph.D. (1992) degrees in Biochemistry and Molecular Biology from Harvard University. He then pursued postdoctoral studies on the role of the RNA binding proteins in Drosophila development at The Whitehead Institute for Biomedical Research, in Cambridge, Massachusetts.

 

Dr. Zamore’s laboratory studies small RNA silencing pathways in eukaryotes and prokaryotes, including RNA interference (RNAi), microRNA, and PIWI-interacting RNA pathways. Dr. Zamore and his collaborators seek to use these insights to design therapies for human diseases, including Huntington’s disease. Under Dr. Zamore’s mentorship, the Zamore Lab has produced dozens of researchers working at top institutions both in the United States and abroad.

 

In 2015, Dr. Zamore was awarded the Chancellor’s Medal for Excellence in Scholarship at the University of Massachusetts Medical School and in 2011, Dr. Zamore was awarded the Dean's award for Research Mentoring and Commitment to Student Professional Development. To date, Dr. Zamore has more than 140 publications and has been among the most highly cited researchers for more than a decade. He serves on the editorial boards of numerous journals and is in demand as a presenter at conferences and institutions worldwide.

 

Dr. Zamore holds more than 20 patents, with other applications pending; he was elected a Fellow of the National Academy of Inventors in 2014. In 2002, Dr. Zamore co-founded Alnylam Pharmaceuticals (Cambridge, MA), a publicly traded biotech company which now has more than 1000 employees and multiple drugs in clinical trials. In 2014, he cofounded Voyager Therapeutics in Cambridge, MA. He serves on the scientific advisory boards of Alnylam, Voyager Therapeutics and ProQR.

 

ADMINISTRATIVE COORDINATOR

Tiffanie Gardner

University of Massachusetts Medical School

Howard Hughes Medical Institute

RNA Therapeutics Institute

Albert Sherman Center

368 Plantation Street

AS4-2045

Worcester, MA 01605

Email: Tiffanie.Gardner@umassmed.edu
Tel:  508-856-6286

Fax: 508-856-6696

LABORATORY MANAGER

Paul Albosta, Ph.D.

University of Massachusetts Medical School

Howard Hughes Medical Institute

RNA Therapeutics Institute

Albert Sherman Center

368 Plantation Street

AS4-2001

Worcester, MA 01605

Email: Paul.Albosta@umassmed.edu
Tel:  508-856-1842

Fax: 508-856-6696

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ZAMORE LAB