The Thévenin group has been awarded two major research grants: A $1.6 million Project Research Grant (R01) from the National Institute of General Medical Sciences of the National Institutes of Health (NIH), and a $300,000 New Initiative grant from The Charles E. Kaufman Foundation. The NIH grant titled “Promoting Receptor Protein Tyrosine Phosphatase Activity by Targeting Transmembrane Domain Interactions” is led by Damien Thévenin and co-principal investigator Matthew Lazzarra (Associate Professor of Chemical Engineering at the University of Virginia). They are joined by collaborating investigator Forest White at the Massachusetts Institute of Technology. The protein at the center of the project is known as protein tyrosine phosphatase receptor type J (PTPRJ), a member of the family of receptor-like protein tyrosine phosphatases (RPTP), which target and dephosphorylate, or deactivate, proteins involved in cell proliferation and survival. The main goal of the project is to understand how to promote the activity of PTPRJ—and eventually other RPTPs—by interfering with the ability of the phosphatase to bind to itself, a process called homodimerization in which two identical proteins form a structure. The Thévenin group has identified a set of mutations and designed small peptide binders that disrupt PTPRJ homodimerization to promote phosphatase activity. Because the phosphatase acts on, and effectively turns off, certain receptors that can promote tumor growth, they think this could eventually lead to a new method to interfere with signaling in cancer cells in a way that would not be circumvented by the common forms of drug resistance seen in cancer treatments. The team also anticipates that their work on the PTPRJ protein will yield insights that are relevant across the receptor-like protein tyrosine phosphatase family. The work funded by the Kaufman Foundation grant (“Full sail ahead: How do cells sense and decode flow?”) is in collaboration with Aurelia Honerkamp-Smith (Assistant Professor of Physics at Lehigh University) and is aimed at understanding how cells from the inner surface of mammalian blood vessels respond to flow, which influences biological processes, such as cardiovascular health and embryonic development. Honerkamp-Smith and Thévenin hypothesize that flow-mediated reorganization of proteins at the surface of cells (similar to sailboats responding to wind) not only encodes information about flow speed and direction, but also initiates intracellular signaling. The two groups will be combining fundamental fluid mechanics and lipid physics with cell signaling and membrane protein biochemistry to quantitatively define the physical and molecular mechanisms that cells use to sense flow and translate this mechanical stimulus into intracellular molecular responses. They anticipate that these studies will not only be applicable to multiple cell lines and flow conditions, but also provide relevant physiological insights into different cardiovascular pathologies and cancers. "Mutations in growth hormone receptors within cancer cells can blunt the effectiveness of cancer drugs. . . This development of resistance happens in most cancers and drugs become ineffective after a relative short period, resulting most often in patient relapse. Since our peptides do not target directly those receptors that are the most susceptible to mutations in cancers, we expect that our strategy will bypass the development of resistance.” -- Damien Thevenin, Lehigh News - May 5, 2021 (Read more) THEVENIN AWARDED TWO MAJOR RESARCH GRANTS Funding from the NIH and the Kaufman Foundation will facilitate next-generation cancer research and treatment Department of Chemistry · Page 3
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