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Anirudh Sivakumar
BME PhD Proposal Presentation
Date:2022-02-07
Time: 2:00 PM
Location / Meeting Link: IBB Suddath Seminar Room 1128 / Virtual Link: https://bluejeans.com/518957531/4900
Committee Members:
Gabe Kwong, PhD (Advisor), M.G. Finn, PhD, Peng Qiu, PhD, Erik Dreaden, PhD, John Blazeck, PhD
Title: Logic-gated activity sensors for programmable cancer diagnostics
Abstract: Advances in synthetic biology are playing a fundamental role in shaping the future of cancer diagnostics toward disease detection and treatment monitoring with higher precision. For example, in engineered T cells, sense-and-respond components that employ AND, OR, or NOT gates have been demonstrated for multiplexed and logical control of T cell responses to increase specificity of tumor-antigen recognition. These advances highlight the promise of synthetic biology for cancer applications, yet the vast majority of these strategies rely on genetic circuits and non-endogenous components, which are complex and may raise safety and immunogenicity concerns for regulatory approval. Therefore, there are outstanding opportunities to apply cell- and gene-free sensors that implement concepts from synthetic biology toward cancer applications. The objective of this thesis proposal is to develop AND-gated protease sensors that integrate design principles from synthetic biology for programmable immune sensing. Protease dysregulation underpins the hallmarks of cancer and immunity and has driven the development of activity-based nanosensors, a class of cell- and gene-free sensors that are administered systemically to query sites of disease and release a reporter upon proteolysis that can be detected in urine. Building on this work, this proposal will design and validate AND-gated activity sensors consisting of nanoparticles conjugated with cyclic peptides that release a reporter only in the presence of protease pairs by implementing AND gate logic. This concept will be tested in the context of anti-tumor T cell immunity. Secretion of proteases called granzymes is fundamental to T cell cytotoxicity but not specific to anti-tumor responses. Therefore, AND-gated sensing of granzymes and cancer-associated matrix metalloproteinases (MMPs) – which are implicated in several fundamental tumor processes – may increase selectivity for detection of anti-tumor immune activity. This proposal will design cyclic peptides that perform AND-gated sensing of granzymes and MMPs (Aim 1), develop mathematical models to predict design parameters that affect specificity (Aim 2), and evaluate urinary biomarkers produced by AND-gated sensors for noninvasive detection of anti-tumor responses to immune checkpoint blockade therapy (Aim 3). This proposal will lay the groundwork for the future design of cell- and gene-free sensors for logic-based cancer diagnostics.
