Download WIMM PI Curriculum Vitae Personal Data Name Tudor Alexandru

WIMM PI
Curriculum Vitae
Personal Data
Name
Nationality
Email
Tudor Alexandru Fulga
ROMANIAN
[email protected]
Present Position
2014-present
Associate Professor, MRC Senior research fellow - WIMM, Radcliffe Department
of Medicine, University of Oxford
Previous Positions
2011-2014
Group Leader, MRC Senior research fellow - WIMM, Radcliffe Department of
Medicine, University of Oxford
2008-2011
Instructor in Cell Biology – Department of Cell Biology, Harvard Medical School,
Boston MA
2004-2007
Postdoctoral Fellow – Department of Pathology, Brigham and Women’s Hospital,
Harvard Medical School, Boston MA. John Douglas French Alzheimer's
Foundation Postdoctoral Fellowship
1998-2003
Ph.D. (PhD title awarded in December 2001) – Structural Biology
Programme/Developmental Biology Programme, EMBL Heidelberg, Germany.
Louis Jeantet PhD Fellow (two fellowships awarded every year for students
across East Europe).
1996-1998
Research Assistant (Undergraduate) – Institute of Biochemistry, Bucharest
Romania
1992-1997
B.Sc. Genetics and Molecular Biology – University of Bucharest, Bucharest,
Romania
RESEARCH ACHIEVEMENTS
During my PhD studies, I initially investigated the process of protein translocation across the ER
and elucidated for the first time the role of the heterodimeric signal recognition particle receptor 
subunit (EMBO J 2001; Science, 2002). Following completion of this work, I focused my attention
on defining the cellular and molecular events controlling the process of cell migration during
development. This research led to the discovery of long cellular extensions (LCE), a remarkable
novel mechanism of force generation in invasive cell migration (Nat Cell Biol., 2002; Nature, 2007).
Later, as a postdoctoral fellow at Harvard Medical School, I investigated the molecular
mechanisms underlying neurodegeneration in Alzheimer’s disease. Amongst several important
scientific contributions to this field, my research delineated the actin cytoskeleton as a critical
mediator of neurodegeneration (Nature Cell Biology, 2006; PLoS Genet. 2010). This discovery
defined a novel mechanism of cytoskeletal cross talk in neurons, and had potential clinical and
therapeutic relevance for Alzheimer’s disease (scientific and media coverage in Nature Reviews
Neuroscience (2007), Nature Cell Biology (2007) and HMS Focus Magazine (2007)). After
completing my postdoctoral studies, I was offered a prestigious Harvard Medical School
Instructorship in Cell Biology. Coincidently, around the same time I became fascinated by the
rapidly growing field of non-coding regulatory RNAs. While the critical role of miRNAs in
development and disease became undisputed, understanding their biological functions lagged
behind, primarily due to limitations in the technologies available for in vivo analysis. To address
this challenge, I pioneered together with Prof. David Van Vactor a highly versatile in vivo
transgenic technology for conditional knock-down of miRNA activity with precise spatial-temporal
resolution (Nature Methods 2009; scientific and media coverage in Nature Methods (2009) and
HMS Focus Magazine (2010)). The conceptual framework of this technology (competitive
inhibition) subsequently became the method of choice in the field for defining tissue-specific
miRNA functions in complex biological systems, and uncovering intricate genetic interactions
between miRNAs and other genes. Additionally, it opened up endless possibilities for dissecting
microRNA regulated pathogenic mechanisms in Drosophila models for human diseases.
WHAT ARE THE FUTURE AIMS OF YOUR CURRENT GROUP?
While tremendous progress has been made in understanding the complexity and importance of
non-coding regulatory RNAs, it is clear that the most significant insights still lie ahead. Our goal is
to decipher the role of non-coding RNAs in development and human diseases, uncover the
molecular mechanisms governing miRNA target recognition and silencing, and engineer innovative
RNA-based synthetic devices for diagnostic and therapeutic applications. Our research
programme is divided in three interconnected modules:
1. miRNA BIOLOGY. The goal of this research is to elucidate the function of miRNAs in animal
development and understand their contribution to certain human pathological conditions. These
studies take advantage of a multi-disciplinary experimental platform combining versatile transgenic
technologies, RNA biochemistry, molecular biology, bioinformatics, advanced imaging, highthroughput genomic tools, and cutting-edge genome engineering technologies. We are particularly
interested in deciphering the role of miRNAs in nervous system development and pathogenesis.
Processes under investigation include neurogenesis, maintaining structural integrity of neuronal
projections, and the molecular mechanisms underlying axonal collapse following traumatic nerve
injury. The fundamental knowledge acquired in these studies may engender new therapeutic
strategies for situations whereby axons have not been transected but are at risk of undergoing
degeneration, such as inflammatory neuropathies, demyelinating conditions (multiple sclerosis),
and certain neurodegenerative disorders.
2. SYNTHETIC BIOLOGY. Cellular reprogramming using synthetic gene networks offers much
promise as a novel therapeutic tool. Underpinning this idea is the need to generate versatile
synthetic devices capable of precise assessment of cellular state and regulation of therapeutic
actuation. A central theme in our group is to repurpose the functionality contained within RNA
molecules to develop molecular devices capable of rewiring cellular behaviour. Attaining this goal
requires a rational design process and in vitro/in vivo evolution strategies, to assemble RNA-based
logic gates into biological computers activated by endogenous triggers. The resulting synthetic
devices have potential for widespread applications ranging from basic tools for miRNA research, to
components in targeted diagnostic and therapeutic strategies. This work falls under the broad
spectrum of synthetic biology, encompassing fields as diverse as biomedical sciences, engineering
and computer sciences.
3. GENOME ENGINEERING. The recent advent of sophisticated genome engineering
technologies such as programmable RNA-guided endonucleases (CRISPR/Cas9), revolutionized
biomedical research and created an unprecedented exploratory landscape for basic research,
disease studies and therapeutic applications. Taking advantage of these technologies, we are
developing novel experimental frameworks for multiplex high-throughput analysis of miRNA activity
in intact biological system. These studies promise to engender unprecedented insight into the
principles and rules governing miRNA target selection in vivo, thus addressing a fundamental, yet
unmet, dimension in miRNA biology. This will enable us for the first time to understand, predict and
assess the impact of miRNAs in the context of a complete gene regulatory network. Our long-term
goal is to elucidate the entire landscape of human miRNA networks in normal versus disease
states, and apply this knowledge to the design of novel miRNA-based therapeutic strategies. In
parallel, we continue to develop new dimensions of genome engineering technologies aimed to
advance their in vivo versatility.
HOW DO THESE AIMS CONTRIBUTE TO THE UNDERSTANDING AND/OR MANAGEMENT OF
HUMAN DISEASE
Because miRNAs are much smaller, less antigenic and display a stereotypical mechanism of
action compared to protein-coding genes, the field of miRNA-based therapeutics is rapidly gaining
momentum. Both miRNA replacement and systemic miRNA inhibition therapies have now entered
clinical trials for a variety of human diseases. For example, the antiviral drug miRavirsen, designed
to recognize and sequester the liver-expressed miR-122, showed unprecedented efficacy in Phase
2a clinical trials against Hepatitis C infection. Similarly, MRX34 (a mimic of the tumor suppressor
miR-34) recently entered Phase 1 clinical trial in patients with unresectable primary liver cancer or
solid cancers with liver involvement. In contrast to the potentially harmful viral-based delivery
methods used for protein-coding genes, miRNA therapeutic agents can be relatively safely
delivered by direct packaging into lipid-based nanoparticles. Although miRNAs appear to have
superior therapeutic potential, their broad transition into clinic remains a challenging task.
Following WIMM’s philosophy of using basic science research to impact medicine and human
health, our research programme aims to generate a more accurate picture on the role of miRNAs
in development, physiology and pathogenesis of human diseases, with the ultimate goal of
translating these discoveries into novel diagnostic and therapeutic strategies. Similarly, the goal of
our synthetic biology programme is to develop RNA-based devices suitable for gene and cell
therapy applications in cancer and infectious diseases. Finally, the recent breakthrough in genome
engineering technologies (CRISPR/Cas9) marked the beginning of a new era of scientific
discovery and molecular medicine applications. Our group is at the forefront of genome
engineering in the UK, being one of the first in Oxford to develop and apply revolutionary designer
nuclease technologies (TALENs and CRISPR/Cas9) towards exploring biological and disease
processes. The relatively straightforward design and streamlined construction protocols developed
for these technologies, together with continuous improvements to increase on-target efficiency and
reduce off-target effects, now offer a realistic opportunity for genome engineering-based
therapeutic applications. Our team is an integral part of a strategic consortium whose remit is to
develop protocols for correcting monogenic mutations in HSPCs, as a promising avenue for
treatment of hematological disorders by autologous transplantation.
LAY SUMMARY OF RESEARCH
Every cell within our body carries the same genetic information, yet following iterative
developmental transitions hundreds of morphologically and functionally distinct cell types are
generated. At the foundation of this fascinating cellular diversification, lies a milieu of finely
orchestrated and sophisticated regulatory programmes, which act to turn on or off thousands of
genes (~20,000 in humans) with minute spatial and temporal precision. Errors in these
programmes can give rise to developmental defects and many human diseases including cancer.
For many years, it was thought that RNAs only function as structural scaffolds and messengers
transferring genetic information from DNA to proteins. This perspective was drastically changed
following the seminal discovery of RNA interference and endogenous non-coding regulatory RNAs.
This discovery revolutionized our view on the regulation of gene expression networks, setting an
important milestone in molecular, developmental and disease biology. While tremendous progress
has been made in understanding the complexity and importance of non-coding RNAs, it is clear
that the most significant insights still lie ahead. Amongst non-coding RNAs, miRNAs provide an
essential gene regulatory layer through binding and tuning the expression of numerous cellular
RNAs via defined “miRNA response elements” (MREs). Central to understanding the cellular
networks regulated by miRNAs, is identification of their direct targets in vivo. This knowledge is also
essential when anticipating the broad consequences of manipulating miRNA function for
therapeutic intervention. Our research programme aims to decipher the role of non-coding
regulatory RNAs in development and human diseases, understand the molecular mechanisms
underlying their activity, and engineer innovative RNA-based synthetic devices for diagnostic and
therapeutic applications.
All Publications Over the Past 5 Years
Fulga T.A.,# et al. Unbiased screening by conditional competitive inhibition reveals novel functions
of conserved Drosophila miRNAs during development and adult behaviour. Developmental Cell.
Under revision.
Tan J.Y., et al. Crosstalking noncoding RNAs contribute to cell-specific neurodegeneration in
Spinocerebellar ataxia type 7. (2014) Nature Structural & Molecular Biology. In press.
Bassett A.R., Azzam G., Wheatley L., Tibbit, C., Rajakumar T., McGowan S., Stanger N., Ewels
P.A., Taylor S., Ponting C.P., Liu J.L., Sauka-Spengler T., Fulga T.A. Understanding functional
miRNA-target interactions in vivo by site-specific genome engineering. (2014) Nature
Communications. Aug 19;5:4640.
Marler K.J., et al. (2014) BDNF Promotes Axon Branching of Retinal Ganglion Cells via miRNA132 and p250GAP. Journal of Neuroscience 34(3):969-79.
Li W., et al. (2013) microRNA-276a functions in Ellipsoid Body and Mushroom Body neurons for
naive and conditioned olfactory avoidance in Drosophila. Journal of Neuroscience 33(13):582133.
Bejarano F., et al (2012) A genomewide transgenic resource for conditional expression of
Drosophila microRNAs. Development, Aug;139(15)
Pathania M., et al (2012) miR-132 Enhances Dendritic Morphogenesis, Spine Density, Synaptic
Integration, and Survival of Newborn Olfactory Bulb Neurons. PLos One, 7(5):e38174.
Khurana V., Merlo P., DuBoff B., Fulga T.A., Sharp K.A., Campbell S.D., Gotz J., and Feany M.B.
(2011) A critical neuroprotective role for an ATM-dependent DNA damage checkpoint. Aging Cell,
11(2):360-2.
Khurana V.,‡ Elson-Schwab I.,‡ Fulga T.A.,‡ Mulkearns M., and Feany M.B. (2010) Lysosomal
proliferation is involved with caspase-cleavage of tau and promotes neurodegeneration in a
Drosophila model of tauopathy. PLoS Genetics, 15;6(7). ‡ Equal contribution
Loya C.M., Van Vactor D., and Fulga T.A. (2010) Understanding neuronal connectivity through the
post-transcriptional toolkit. Genes and Development, 24(7):625-35
Loya C.M., Lu C.S., Van Vactor D.,# and Fulga T.A.# (2009) Transgenic microRNA inhibition with
spatiotemporal specificity in intact organisms Nature Methods, 6(12):897-903.
Chang H., et al. (2008) Modeling Spinal Muscular Atrophy in Drosophila PLoS ONE 15;3(9):e3209
Fulga T.A.# and Van Vactor D.# (2008) Synapses and growth cones on two sides of a highwire
Neuron 57(3):339-44.
Bianco A., et al (2007) Two distinct modes of guidance signaling during collective migration.
Nature 448 (7151):362-5.
Ten Key Publications Throughout your Career
Tan J.Y., et al. Crosstalking noncoding RNAs contribute to cell-specific neurodegeneration in
Spinocerebellar ataxia type 7. (2014) Nature Structural & Molecular Biology. In press.
Bassett A.R., Azzam G., Wheatley L., Tibbit, C., Rajakumar T., McGowan S., Stanger N., Ewels
P.A., Taylor S., Ponting C.P., Liu J.L., Sauka-Spengler T., Fulga T.A. Understanding functional
miRNA-target interactions in vivo by site-specific genome engineering. (2014) Nature
Communications. Aug 19;5:4640.
Khurana V.,‡ Elson-Schwab I.,‡ Fulga T.A.,‡ Mulkearns M., and Feany M.B. (2010) Lysosomal
proliferation is involved with caspase-cleavage of tau and promotes neurodegeneration in a
Drosophila model of tauopathy. PLoS Genetics, 15;6(7). ‡ Equal contribution
Loya C.M., Lu C.S., Van Vactor D.,# and Fulga T.A.# (2009) Transgenic microRNA inhibition with
spatiotemporal specificity in intact organisms Nature Methods, 6(12):897-903.
Steinhilb M.L., Dias-Santagata D.,‡, Fulga T.A.,‡, Felch D.L., and Feany M.B. (2007) Tau
phosphorylation sites work in concert to promote neurotoxicity in vivo Mol. Biol. Cell 18(12):50608 ‡ Equal contribution
Bianco A., Cliffe A., Poukkula M., Mathieu J., Luque C.M., Fulga T.A., and Rørth P. (2007) Two
distinct modes of guidance signaling during collective migration. Nature 448 (7151):362-5.
Fulga T.A.,# Elson-Schwab I., Khurana V., Steinhilb M.L., Spires T.L., Hyman B.T., and Feany
M.B.# (2006) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal
degeneration in vivo. Nature Cell Biology, 9(2):139-48. # Corresponding author
Fulga T.A. and Rørth P. (2002) Invasive cell migration is initiated by guided growth of long cellular
extensions. Nature Cell Biology 4(9):715-719
Pool M.R., Stumm J., Fulga T.A., Sinning I. and Dobberstein B. (2002) Three stages in Signal
Recognition Particle interaction with the Ribosome Science 297(5585):1345-8
Fulga T.A., Sinning I., Dobberstein B. and Pool M.R. (2001)
release from SRP with Ribosome binding to the Translocon. EMBO J. 20(9):2338-47
Markers of Esteem
2011
MRC Senior Research Fellowship
2010
HMS/HSMD Postdoctoral Fellow Travel Award
2009
F-1000 faculty member
2008
Keystone Symposia Scholarship
2007
BWH & HMS Award for outstanding achievement in science research
2006
John Douglas French Alzheimer's Foundation Postdoctoral Fellowship
2005
Harvard University Award of Distinction in Teaching
2002
Best Poster Prize – Santa Cruz Conference on Developmental Biology
1998
Louis Jeantet PhD Fellowship for East Europe (EMBL Heidelberg)
Current Grant Support
MRC Senior Research Fellowship 2011-2016
£ 1,100,688
MRC Confidence in Concept Award 2013-2014
£ 80,640
NDM/WT Research Fund
£ 9,076
BBSRC Research Project Grant 2014-2016
£ 482,98