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Neal Silverman, Ph.D.
Academic Role: Associate Professor
Faculty Appointment(s) In:
Infectious Diseases and Immunology
Medicine
Other Affiliation(s):
Center for AIDS Research
Interdisciplinary Graduate Program
Program in Immunology and Virology
Rotation Projects
Intro:
Like us, insects recognize pathogenic microorganisms and
respond with potent antimicrobial defenses. Insects have only a primitive
immune system which relies solely on germline encoded receptors to recognize
various microbial derived substances. Mammals have similar system, known as
the innate immune response, that plays a critical role in recognizing dangerous
pathogens and activating the more complicated adaptive immune response
involving antigen presentations and T- and B-cell receptors. Insect and
mammalian innate immunity have much in common. For example, they both use the
NF-kB /Rel family of transcription
factors to rapidly activate immune inducible gene expression. Drosophila has
three NF-kB homologs, all of which are
involved in immunity. One Drosophila NF-kB,
known as Relish, is activated by proteolytic cleavage in response to infection
with gram-negative bacteria. The other two NF-kB
homologs, Dorsal and Dif, are activated during a fungal (or gram postive
bacterial) infection when their inhibitor, known as Cactus (IkB) is degraded. The focus of the lab is to
understand the underlying molecular mechanisms responsible for activation of
specific NF-kB transcription factors in
response to different pathogens.
- Goal: To examine the role of all seven Drosophila caspase
proteases in the activation of immunity. Relish is activated by
caspase-mediated proteolysis, but the protease that cleaves Relish is not
yet identified. This experiment will use RNAi to inhibit caspase gene
function in an immune responsive Drosophila cell line, followed by
analysis of the immune-inducible gene expression. This project is
designed to identify which caspase proteases are required for Relish
activation. Further experiments will be designed to demonstrate the
direct cleavage of Relish by caspase proteases.
- Goal: Genome wide analysis of the insect immune
response. In this project we will utilize Drosophila cDNA microarrays to
study the changes in gene expression induced by immunostimulatory
molecules. In particular, we will analyze the activity of various
microbial derived products to illicit specific immune responses. Also, we
will examine if the role of different signaling pathways in the immune
response, especially the JNK and NF-kB
signaling pathways.
- Goal: To genetically characterize the function of the
second Drosophila IKK homolog, IKKe.
The function of human and Drosophila IKKe
remains controversial. Drosophila IKKe
mutants do not survive to adulthood. This project will focus on studying
the role of Drosophila IKKe in the
developing embryo, by studying its expression pattern and by making
germliine clones. In the long term, we hope to determine the role, if
any, of DmIKKe in the activation
of NF-kB family transcription
factors in Drosophila.
- Goal: To use Drosophila genetics to understand the
pathogenesis of the plague. In this project, we will establish transgenic
flies that express YopJ, a protein from the plague pathogen Yersinia
pestis. In mammals, YopJ blocks important signaling pathways, such as
NF-kB, and thus prevents immune
activation. Although, YopJ has been proposed to be a ubiquitin-like
protein protease (ULP), the molecular mechanisms by which YopJ functions
are unclear. We will demonstrate in flies that YopJ blocks immune
activation of NF-kB. Further
genetic experiments will be designed to test the possibility that YopJ
acts as a ULP. Ultimately, forward genetic screens will be performed to
identify genes required for YopJ function.
Office: LRB 313
Phone: 508-856-5826
Fax: 508-856-5463
E-mail: Neal.Silverman@umassmed.edu
Keywords:
Immunology,
Genetics,
Organisms - Drosophila,
Infectious Disease,
Gene Regulation
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55 Lake Avenue North Worcester, MA 01655