Elucidating molecular and cellular transport mechanisms of the innate immunotransmitter cGAMP for paracrine STING signaling
Abstract/Contents
- Abstract
- The innate immune system represents a crucial first-line of defense against infection and disease. Moreover, the quality and quantity of the innate immune response shapes the subsequent adaptive immune response in dramatic ways. As a result, uncovering the mechanisms by which innate immunity is activated has broad implications not only for understanding cellular and organismal biology, but also for the development of powerful immunotherapeutic drugs. One innate immune pathway, the cGAS-STING pathway, has been implicated as a major factor across diverse contexts in human health: protection against viral infection, response to cancer and cancer therapies, and also pathogenic autoinflammatory and autoimmune states. A unique aspect of the cGAS-STING pathway is that activation of the sensor and receptor are linked by the production of a distinct small molecule second messenger, 2'3'-cyclic GMP-AMP (cGAMP). While cGAMP plays important roles within a single cell, striking biological effects are observed when cGAMP is able to "spread the message" that innate immunity should be activated across cells throughout in the local environment. This dissertation focuses on paracrine cGAS-STING signaling mechanisms and therapeutic applications in detail. In Chapter 1, I will review the molecular mechanisms of the cGAS-cGAMP-STING pathway, its signal transduction, and implications in human health and disease. In Chapter 2, I will describe the identification of LRRC8A:C/E heteromeric channels as widely-expressed, bidirectional transporters of cGAMP that enable cGAMP's paracrine signaling function. In Chapter 3, I will report ongoing efforts to develop cGAMP as a vaccine adjuvant through the use of hydrogels to control cGAMP release and delivery in a highly localized manner.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lahey, Lauren J |
|---|---|
| Degree supervisor | Li, Lingyin |
| Thesis advisor | Li, Lingyin |
| Thesis advisor | Kim, Peter, 1958- |
| Thesis advisor | Rohatgi, Rajat |
| Degree committee member | Kim, Peter, 1958- |
| Degree committee member | Rohatgi, Rajat |
| Associated with | Stanford University, Biophysics Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Lauren Jessica Lahey. |
|---|---|
| Note | Submitted to the Biophysics Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/bs735yg2454 |
Access conditions
- Copyright
- © 2021 by Lauren J Lahey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial No Derivatives 3.0 Unported license (CC BY-NC-ND).
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