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 Matthew
Weitzman,
Ph.D.
Associate Director
Center for Cellular and Molecular Therapeutics
Office Address:
The Children’s Hospital of Philadelphia
302B Abramson Research Center
3615 Civic Center Blvd
Philadelphia, PA 19104-4318
TEL 267-425-2068
LAB 267-426-9147
FAX TBA
weitzmanm@email.chop.edu
PI Website
Lab Website
RESEARCH SUMMARY
Our lab studies the interactions between viruses and their host cells. Viruses
try to hijack cellular machinery to aid their own replication, but the host
cell often responds with defense systems that can create obstacles for the
virus. Watching these battles unfold has contributed significantly to
our understanding of fundamental cellular mechanisms and has established viruses
as powerful model systems to study cell biology.
We have a particular interest in the interactions between viruses and the DNA
repair pathways of the host cell. The work in my lab addresses the fundamental
question of how the human genome maintains integrity in the face of viral genetic
assault. Viral genomes pose a direct threat to the host genome. During
infection a battle ensues in which both host and viral genomes must each be protected
to maintain their genetic integrity. We study the dynamic interactions
between viruses and host cells when their genomes are in conflict. My lab
discovered that the cellular apparatus that resolves DNA damage also acts as
a defense against viral assault. The sophisticated surveillance network for sensing
and repairing DNA prevents an array of human diseases. When compromised
it results in genomic instability that ultimately leads to cancer. We are
studying how the cellular damage sensing machinery as an intrinsic defense to
virus infection, and ways in which viruses mount a counterattack by dismantling
the cellular DNA repair machinery or even exploiting it to aid their own
replication. In addition to understanding virus-host interactions, studying
DNA repair together with the natural process of virus infection provides a platform
for interrogating cellular pathways involved in recognition and processing of
DNA damage.
We are exploring multiple viruses in an integrated experimental approach that
combines biochemistry, molecular biology, genetics and cell biology. We
have chosen viral models that provide tractable systems to investigate the dynamic
interplay between viral genetic material and host defense strategies. We
study Adenovirus (Ad), Herpes Simplex Virus (HSV-1), and Adeno-Associated Virus
(AAV). These viruses each have different types of DNA genomes and have
developed distinct ways of manipulating host defenses.
Unraveling the complex host cell response to invading viral genomes has broad
implications. The pathways illuminated are key to fighting diseases of
both viral infection and genome instability. Our studies on repair and
silencing of viral genomes have significant implications for the development
of efficient viral vectors for gene therapy. Viral complexes that manipulate
host pathways reveal novel ways in which protein modifications regulate diverse
processes. The conflicts between virus and host also impact and inform
us about the evolution of our genome.
Current projects:
We have an interactive and collaborative lab environment where students and postdocs
are encouraged to explore multiple projects and challenge each other intellectually. Ongoing
projects include:
- Impact of DNA damage responses on virus infection and gene delivery
- Identifying targets for viral encoded ubiquitin ligases
- Roles for post-translational modifications in regulating viruses
- Epigenetic changes during virus infection
- Identifying host restriction factors during virus infection
- Defining functions for the cellular APOBEC proteins
- Exploiting viral manipulation of cellular pathways to improve gene targeting
and gene therapy
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