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Chemical and Optochemical Control of Cell Signaling

Ryan, Amy (2022) Chemical and Optochemical Control of Cell Signaling. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Signal transduction pathways are responsible for maintaining cellular functions, including proliferation, differentiation, apoptosis, and cell cycle progression. These pathways are maintained through intricate signaling mechanisms, such as through signal propagation by kinases and phosphatases, targeted protein translocation, and protein degradation by E3 ligases. Light can be used as a powerful tool for the precise spatiotemporal regulation of these processes in live cells, particularly in combination with the complete genetic specificity of unnatural amino acids. Here I describe my contributions towards: (1) the application of two photocaged amino acid analogues for optical control of phosphatase activity through enzymatic and functional perturbation, (2) the design and optimization of two novel tools for genetically encoded, light-triggered protein degradation, and (3) the development of a novel method for light-induced protein translocation using photocaged phosphoinositide binding motifs.

Additionally, I have contributed to the demonstration of hydrogen peroxide-mediated cytotoxin release in vitro and in vivo. Aberrant cell signaling leads to the progression of disease, and chemical tools aid in both understanding these processes and treating the disease. Prodrugs are therapeutic small molecules which are selectively released through chemical or enzymatic conversion to the active compound. Boronate-masked prodrugs are sensitive to high-redox environments, a hallmark characteristic of cancer cells, enabling delivery of the parent molecule upon exposure to hydrogen peroxide. Here I describe the real-time evaluation of intracellular hydrogen peroxide stimulation and its application to the selective release of three novel prodrug molecules.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ryan, Amyaer80@pitt.eduaer80
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDeiters, Alexanderdeiters@pitt.edudeiters
Committee MemberWeber, Steven Gsweber@pitt.edusweber
Committee MemberChilders, W Sethwschild@pitt.eduwschild
Committee MemberHammond, Gerald RVghammond@pitt.edughammond
Date: 12 October 2022
Date Type: Publication
Defense Date: 27 May 2022
Approval Date: 12 October 2022
Submission Date: 27 July 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 272
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: optochemical, optical control, optogenetic, cell signaling
Date Deposited: 12 Oct 2022 16:20
Last Modified: 12 Oct 2022 16:20


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