BioMT funds four research projects led by outstanding junior faculty members. Each project focuses on identifying, validating, and inhibiting key cellular pathways. Our goals are to illuminate fundamental biological mechanisms and provide novel strategies to target devastating diseases. Each research advance will also lay the foundation for independent extramural grant applications.
Proteomic Approaches to Target the PP6-mTORC2 Pathway in Glioblastoma
Description: Glioblastoma multiforme (GBM) is the most common and aggressive tumor of the central nervous system in adults and it is generally fatal within 12 months of diagnosis. We propose to identify targets in the newly uncovered and frequently overexpressed PP6-mTORC2 pathway for the development of new therapeutic strategies to fight this devastating disease.
Identifying Mitophagy Receptors as Targets in Ras-dysregulated Cells
Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and challenging cancers to treat in the United States. The growth of PDAC tumors is dependent on a cellular degradation process, termed autophagy. We are combining biochemical and cellular approaches to uncover the role of autophagy in PDAC.
Protein Design for Selective Interference with LPA Signaling in Colon Cancer
Description: Colorectal cancer was the third-most common cause of deaths from cancer in the United States in 2013. This disease claims over 50,000 lives and afflicts over 140,000 people annually in the US, underscoring a clear and urgent need for better control of this incurable malignancy. The goal of our study is to attenuate oncogenic activities in colon cancer cells by inhibiting a key proliferatory signaling pathway mediated by the powerful mitogen lysophosphatidic acid (LPA). Key towards this goal is to produce selective inhibitors—molecules that interact with and inhibit specific proteins in the cell, while avoiding any unintended side-interactions with other proteins. We are uniquely capable of providing such selectivity using computational technologies we have developed that enable us to target selectively a single member in a family of closely related protein domains.
Molecular Mechanisms of RSV F Activation and Inhibition
Description: Respiratory syncytial virus (RSV) causes respiratory tract infections that result in substantial morbidity and mortality in infants and the elderly. RSV entry into host cells is facilitated by an attachment protein (G) and a fusion protein (F) that in its active form adopts a metastable prefusion conformation. After attachment of RSV to cells, it is hypothesized that host-factors trigger the conformational rearrangement of F that results in fusion of the viral and cellular membranes. The prefusion conformation of F is therefore considered an ideal vaccine antigen, and antibodies and small molecules that disrupt its structure and function are actively being pursued. Development of effective therapeutics will be greatly enhanced by a molecular understanding of how the F glycoprotein interacts with host-cell factors to promote entry, and how neutralizing antibodies inhibit one or more steps in the entry process. For this project, we will test two hypotheses: first, that specific host-cell factors enhance the rate of RSV F triggering; and second, that the most potent neutralizing antibodies target receptor-binding sites and block conformational changes. We expect that the results from these studies will fill important gaps in our understanding of RSV entry and provide a molecular basis for RSV F activation and inhibition.