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Mechanisms of Innate Immune Activation by Cytotoxic Chemotherapeutics.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Mechanisms of Innate Immune Activation by Cytotoxic Chemotherapeutics./
作者:	Flynn, Patrick.
面頁冊數:	1 online resource (121 pages)
附註:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29169444click for full text (PQDT)
ISBN:	9798819381076

Mechanisms of Innate Immune Activation by Cytotoxic Chemotherapeutics.
Flynn, Patrick.

Mechanisms of Innate Immune Activation by Cytotoxic Chemotherapeutics. - 1 online resource (121 pages)

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

Mitotic errors and DNA damage produce damage-associated molecular patterns(DAMPs) which can activate pattern recognition receptors (PRRs) and elicit innate immune responses in the form of inflammation. Inflammation can cause tumor regression and enhance the effects of cancer therapy. cGAS is an important anti-viral PRR that causes type 1 IFN signaling in response to DNA DAMPs. cGAS activation is implicated in generating therapeutic anti-tumor inflammation in response to chemotherapy and irradiation.However, the origins of DNA DAMPs and mechanisms of cGAS activation are poorly understood.We used a panel of anti-mitotic drugs to study the mechanisms of cGAS activation after mitotic errors. We developed a series of co-culture assays to measure cGAS activation and IFN signaling. Using these assays, we observed that microtubule stabilizers and MPS1 inhibitors are the only anti-mitotic drugs able to activate cGAS in a non-transformed fibroblast model. We propose that cGAS is selectively activated by DNA when it is stretched in chromatin bridges. cGAS localization inside micronuclei failed to predict cGAS activation. This project is described in Chapter 1.In Chapter 2, we studied cGAS activation in response to DNA-damaging chemotherapeutics.We observed that drugs which cause direct DNA damage fail to activate cGASin non-transformed fibroblasts, but can activate cGAS in cancer and mouse cells. We then explored mechanisms of cGAS activation by studying a panel of topoisomerase II (topoII)inhibitors that produce distinct forms of cellular damage. Our data show species-specific activation of murine cGAS in response to catalytic topoII inhibition. We propose that cGAS does not typically activate in response to DNA damage in healthy human cells, and mouse and human cGAS can respond differently to DAMPs generated by chemotherapy.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798819381076Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Anti-mitoticsIndex Terms--Genre/Form:

542853
Electronic books.

Mechanisms of Innate Immune Activation by Cytotoxic Chemotherapeutics.
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