Access Type

Open Access Embargo

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biomedical Engineering

First Advisor

Juri G. Gelovani

Abstract

Over the past two decades, epigenetic regulation has become a rapidly growing, highly innovative and influential field of biology and medicine. Protein acetylation and deacetylation, two key epigenetic regulatory mechanisms, are mediated by histone acetylase transferases (HATs) and histone deacetylases (HDACs), respectively. To date, the vast majority of studies on epigenetic regulation have been conducted in cell cultures and tissue samples using conventional methodologies of molecular and cellular biology, which contain inherent limitations for monitoring therapy and disease. Therefore, there is a growing need for novel, advanced methodologies that allow for non-invasive detection and monitoring of HDAC–mediated epigenetic regulatory processes in different organs and tissues. One such methodology is molecular imaging with positron emission tomography (PET), which allows for non-invasive visualization and quantification of spatial and temporal dynamics of expression-activity of various receptors and enzymes in different organs and tissues in norm and disease. The availability of selective substrates to various classes and isoforms of HDACs would enable the development of radiolabeled imaging agents for non-invasive in vivo PET imaging. Therefore, the aim of this work is to develop class- and/or isoform-selective radiolabeled substrates of HDACs, with particular emphasis on class III (sirtuins, SIRTs).

Herein, HDAC class IIa, SIRT1 and SIRT2-selective radiotracers have been developed and validated through in vitro and in vivo characterization. Two of these tracers, 18F-TFAHA for HDAC class IIa and and 2-[18F]PhAHA for SIRT1, have also been validated in a disease model demonstrating their utility in understanding epigenetic regulation in an aggressive form of brain cancer. The development of these targeted imaging agents may help develop new therapies for disease as well as methodologies for monitoring treatment effectiveness and disease progression.

Available for download on Thursday, December 07, 2017

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