2012-2013 CAFA Faculty Development Grants

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The Robert T. Poe Faculty Development Grant

Jikui Song, Assistant Professor, Biochemistry Department, University of California, Riverside

Structure and regulatory mechanisms of DNMT1-mediated epigenetic inheritance

Our long-term goal is to provide a comprehensive understanding of how the DNA methylation machinery is regulated and the relationship of this regulation to DNA methylation patterns and human disease processes. The objective of this application is to determine the structural basis for the substrate specificity of the DNMT1 MTase domain, and to identify the roles of the DNMT1 N-terminal domains and other proteins in regulating the enzymatic function of DNMT1. Our central hypothesis is that the enzymatic function of DNMT1 is orchestrated by a multifaceted regulation. We formulate this hypothesis, in part, based on our preliminary data demonstrating that the enzymatic activity of DNMT1 is regulated via a multi-layered mechanism. We will employ biochemical, molecular biological and structural approaches to investigate the regulatory mechanisms of DNMT1, with focus on two specific aims: 1) Illustrate the molecular basis underlying the substrate preference of the DNMT1 MTase domain; and 2) Reveal the intramolecular regulatory mechanism of DNMT1.

The CAFA Faculty Development Grant

Yong Xue Gan, Associate Professor, Department of Mechanical Engineering, Cal Poly Pomona

Fundamental studies on the combined effect of thermotherapy and chemotherapy for early-stage cancers using functionalized composite nanotubes

The objective of this project is to explore the feasibility of combining chemotherapy with hyperthermia in early-stage cancer treatments using functionalized multilayered nanotubes. Adjuvant administration of chemical therapy with hyperthermia in cancer treatments has been proposed for years, but their simultaneous delivery through the same treatment source has not been reported. In this research, fundamental studies to determine the feasibility of the development and implementation of a new thermo-chemotherapy core-shell nanotube seed that consists of an encapsulated drug delivery core with a ferromagnetic shell. When implanted in tissue and inducted by a controlled external electromagnetic field, the shell of the nanotube seed will self-regulate heat output. The combination of an electromagnetic field and a self-regulating heat feature will preclude the need for invasive thermometry and ease heat delivery, especially to deep-seated tumors. This is especially suitable for treating early stage cancers because the damage to normal tissue could be controlled at the minimum level. The ferromagnetic shell will be iron oxide or nickel oxide loaded titanium dioxide nanotubes made from electrochemical oxidation of titanium. Drugs for chemotherapy will be injected into the nanotube. Delivering the drug will be realized by the induction heating of the shell at the onset of cancer therapy. The shell of the seed could also be used for thermal treatment of a tumor. If the project is successful, the nanotube seed could serve as a sensitizer to systemic therapies without another invasive procedure.

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