ZAMORE LABORATORY

OUR RESEARCH

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Argonautes are the only known family of proteins that can be programmed with any RNA or DNA sequence to make sequence-specific regulators of transcription, mRNA stability, or translation. Our lab seeks to understand the biology and mechanism of paradigmatic examples of Argonaute proteins and pathways, and, ultimately, to use these insights to design and improve small RNA-guided therapies for human diseases. Indeed, studying how Argonautes work and how their small RNA guides are made has led to the development and FDA approval of small RNA drugs. Nevertheless, fundamental questions about the specificity and function of Argonaute protein-mediated pathways remain unanswered.

Despite >20 years of study, for example, we still cannot predict how Dicer enzymes will cleave a pre- miRNA based only on its sequence. We will use biochemical and structural approaches to identify the features that determine where Dicer cleaves a pre-miRNA and how Dicer partner proteins alter this process.

In animals, the PIWI subfamily of Argonaute proteins uses 23–30-nt “piRNA” guides to silence transposons or regulate gene expression in germ cells. piRNAs are made from specific long, single-stranded precursor RNAs. Our research seeks to explain why some genomic regions and transcripts are destined to make piRNAs, while others are excluded. By studying piRNAs in flies, moths, and mice, we hope to identify both evolutionarily ancient and newly evolved strategies that animals use to designate piRNA precursors and to convert them into functional complexes with PIWI proteins. While experimental and computational studies have dramatically improved our ability to predict miRNA targets, similar advances have not yet been made for piRNAs. In the spermatocytes of placental mammals, pachytene piRNAs are nearly as abundant as ribosomes, but we still do not know what or how they regulate. Mutations in the proteins that make pachytene piRNAs cause male infertility, suggesting that pachytene piRNAs promote sperm development. We use biochemistry and mouse genetics to study the function and specificity of pachytene piRNAs.

Finally, many archaeal and bacterial genomes encode Argonautes, yet we rarely know what they do or how they acquire their guides. Some Argonautes, such as Thermus thermophilus Ago, even use DNA guides to target DNA. Understanding the function of bacterial Argonaute proteins will not only broaden our evolutionary understanding of this remarkable protein family, but may ultimately lead to the development of novel antibiotics.

 

 

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 150 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. Alnylam’s first drug, ONPATTRO, a first-of-its-kind RNAi therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, was approved by the FDA in 2018. In 2014, he co-founded Voyager Therapeutics in Cambridge, MA. 

 

HHMI ADMINISTRATIVE COORDINATOR
Certified Associate in Project Management

Tiffanie Gardner, CAPM

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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