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- West Virginia University School of Medicine
Program 1: Mechanisms of Metastasis & Therapeutic Response Program (MMTR)
Luanpitpong S, Wang L, Davidson DS, Riedel H, Rojanasakul, Y (2016) "Carcinogenic potential of high aspect ratio carbon nanomaterials". Environ Sci Nano 3, 483
Rahman SH, Kuehle J, Reimann C, Mlambo T, Alzubi J, Maeder ML, Riedel H, Fisch P, Cantz T, Rudolph C, Mussolini C, Joung JK, Schambach A, Cathomen T (2015) "Rescue of DNA-PK signaling and T-cell differentiation by targeted genome editing in a prkdc deficient iPSC disease model". PLoS Genet 11, e1005239. doi: 10.1371/journal.pgen.1005239. eCollection 2015
Ma JX, Yan BX, Zhang J, Jiang BH, Guo Y, Riedel H, Mueller MD, Remick SC, and Yu JJ (2014) "PSP94, an upstream signaling mediator of prostasin found highly elevated in ovarian cancer". Cell Death and Disease 5, e1407; doi:10.1038/cddis.2014.374
B-x Yan, J-x Ma, J Zhang, Y Guo, H Riedel, Mueller M, Remick S, and Yu JJ. "PSP94 contributes to chemoresistance and its peptide derivative PCK3145 represses tumor growth in ovarian cancer". Oncogene doi:10.1038/onc. 2013. 466.
Zhang M, and Riedel, H (2010) "Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1". J Cell Biochem, 107, 65-75.
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.
Riedel, H. (2004) "Grb10: Exceeding the boundaries of a common signaling adapter". Front. Biosci. 9, 603-618.
Mechanisms of Metastasis & Therapeutic Response and Metastasis Breast Cancer
Areas of Research: Cancer and Diabetes
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.