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Heimo Riedel, Ph.D.
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Professor
PhD: EMBL and University of Heidelberg, Germany
Postdoctoral Training: Genentech
Joined the faculty:
2003
Affiliations: MBR
Cancer Center
Teaching: MS1 PBL,
CCMD 793M, CCMD 793L, CCMD 793Q, BIOC 339, BIOC 693
Office: 3100
Phone: (304) 293-1669
Fax: (304) 293-6846
Email: hriedel@hsc.wvu.edu |
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Research Interests: |
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Areas of Research: |
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Cancer and Diabetes |
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Research Program: |
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A key goal in
biomedicine is the development of new therapies for diseases. Cancer
and Diabetes rank highly on a global scale. Aspects of both diseases
result from alterations in the cellular signaling circuitry that is
critical to coordinate the normal cellular processes within one cell
and between individual cells in tissues and organs. The research
focus of this team is to unravel the wiring of key signaling
circuits and the underlying networks and molecular mechanisms that
play a role in these diseases as well as in normal cell regulation.
We are defining key mechanisms of the same fundamental circuitry
that regulates diverse cellular processes in cell proliferation,
survival and malignant transformation, cell migration, invasion,
wound healing, and metabolism in diverse environments and organs
from the liver to the central nervous system as well as in
developmental programs.
The first newly
funded project is focused on a radically new approach that exploits
modern biotechnology tools to directly attack human pathogens with
cell-permeant zinc finger nucleases, molecular scissors that will
specifically disrupt the genome of the pathogen. This approach could
eventually replace standard vaccine-based disease protocols. It is
initially focused on human papillomavirus (HPV) the causal agent of
cervical cancer to establish the feasibility of the proposed
strategy. Current treatment of infectious diseases is typically
based on the concept of activating a host immune response after
application of a vaccine or alternatively, of interfering with the
propagation of the pathogen with a drug such as an antibiotic.
Modern biotechnology provides us with rapidly evolving tools to
specifically attack the genome of a pathogen directly based on its
unique nucleic acid sequence with custom-made zinc finger nucleases
(for more information see Pearson 2008 Nature 455, 160). These can
act as specific molecular scissors targeting and disrupting a
specifically chosen and unique pathogen sequence that results in
functional inactivation and potential elimination of the pathogen.
We will design and test cell-permeant zinc finger nucleases that
will enter cells by crossing the cell membrane, specifically bind to
and disrupt unique pathogen sequences, and prevent pathogen
function. Initially, our target will be human papillomavirus (HPV)
either in its episomal form or when integrated into the human
genome. Once validated this approach can be adapted to many other
human pathogens or diseases including Malaria, Pneumonia, or
Tuberculosis.
The second project
has discovered and will define an alternative signaling mechanism of
the insulin receptor (IR) that is independent of its tyrosine kinase
activity. This mechanism has likely evolved prior to the
well-established catalytic IR signal based on data in lower
eukaryotes but remained obscure at the molecular level. We have
begun to establish its molecular basis in mammals by defining an
alternative insulin signal that results in Tyr phosphorylation and
catalytic activation of phosphatase PHLPP1 via a PI
3-kinase-independent, wortmannin-insensitive signaling pathway.
Dimerized signaling adapter SH2B1/PSM is a critical activator of the
IR kinase and the resulting established insulin signal. In contrast,
it is an inhibitor of the IR kinase-independent insulin signal and
disruption of SH2B1/PSM dimer binding to IR potentiates this signal.
Dephosphorylation of Akt2 by PHLPP1 provides an alternative, SH2B1/PSM-regulated
insulin-signaling pathway from IR to Akt2 of opposite polarity and
distinct from the established PI 3-kinase-dependent signaling
pathway via IRS proteins. In combination, both pathways should allow
the opposing regulation of the amplitude and duration of Akt2
activity at two phosphorylation sites to specifically define the
insulin signal in the background of interfering Akt-regulating
signals, such as those controlling cell proliferation and survival.
This project has been developed with funding from the National
Cancer Institute and from the American Diabetes Association.
The underlying
mechanisms are of broad significance and shared by the key signaling
circuitry that controls development, differentiation, growth and
metabolism in most animals. Our research can be applied to efforts
in the biotechnology and pharmaceutical industries to design
specific molecular therapies or diagnostics. Our work has resulted
in patents and licensing fees from the biotechnology industry, about
a hundred research papers (see list of 6 selected articles) and has
been supported by twenty major research grants and fellowships from
government and private sources and foundations. Former trainees in
the program have secured positions in academia including independent
academic faculty positions and in industry including responsibility
for large laboratories. Successful applicants can expect to obtain
rigorous training in modern molecular genetics, cell biology,
bioinformatics, and proteomics, to significantly expand their
publication list, and to develop the skills and the expertise needed
to succeed in the biotechnology industry or in a career towards an
independent academic position. |
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References:
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- Riedel, H. (2004) Grb10: Exceeding
the boundaries of a common signaling adapter. Front. Biosci. 9,
603-618.
- Deng Y, Xu H, and Riedel H (2006)
PSM/SH2-B distributes selected mitogenic receptor signals to
distinct components in the PI3-kinase and MAP kinase signaling
pathways. J Cell Biochem 100, 557-573.
- Riedel H (2007) Models for tumor
growth and differentiation. In The Cancer Handbook Vol. 2. 4:
Pre-clinical models for human cancer (ed Alison MA), 954-969 Nature
Publishing Group, London.
- Zhang M, Deng Y, Tandon R, Bai C,
and Riedel, H (2008) Essential role of PSM/SH2B1 variants in insulin
receptor catalytic activation and the resulting cellular responses.
J Cell Biochem, 103, 162-181.
- Zhang M, Deng Y, and Riedel, H
(2008) PSM/SH2B1 splice variants: critical role in Src catalytic
activation and the resulting STAT3-mediated mitogenic response. J
Cell Biochem, 104, 105-118.
- Deng Y, Zhang M, and Riedel, H
(2008) Mitogenic roles of Gab1 and Grb10 as direct cellular partners
in the regulation of MAP kinase signaling. J Cell Biochem,
105,1172-1182.
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