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Genomic approaches to dissect innate...

Lee, Mark N.

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Genomic approaches to dissect innate immune pathways.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Genomic approaches to dissect innate immune pathways./
Author:	Lee, Mark N.
Description:	133 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
Contained By:	Dissertation Abstracts International74-06B(E).
Subject:	Health Sciences, Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3553439
ISBN:	9781267929167

Genomic approaches to dissect innate immune pathways.
Lee, Mark N.

Genomic approaches to dissect innate immune pathways. - 133 p.

Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2013.

The innate immune system is of central importance to the early containment of infection. When receptors of innate immunity recognize molecular patterns on pathogens, they initiate an immediate immune response by inducing the expression of cytokines and other host defense genes. Altered expression or function of the receptors, the molecules that mediate the signal transduction cascade, or the cytokines themselves can predispose individuals to infectious or autoimmune diseases. Here we used genomic approaches to uncover novel components underlying the innate immune response to cytosolic DNA and to characterize variation in the innate immune responses of human dendritic cells to bacterial and viral ligands.

ISBN: 9781267929167Subjects--Topical Terms:

1017716
Health Sciences, Immunology.

Genomic approaches to dissect innate immune pathways.
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020 $a 9781267929167
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245 1 0 $a Genomic approaches to dissect innate immune pathways.
300 $a 133 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
500 $a Adviser: Nir Hacohen.
502 $a Thesis (Ph.D.)--Harvard University, 2013.
520 $a The innate immune system is of central importance to the early containment of infection. When receptors of innate immunity recognize molecular patterns on pathogens, they initiate an immediate immune response by inducing the expression of cytokines and other host defense genes. Altered expression or function of the receptors, the molecules that mediate the signal transduction cascade, or the cytokines themselves can predispose individuals to infectious or autoimmune diseases. Here we used genomic approaches to uncover novel components underlying the innate immune response to cytosolic DNA and to characterize variation in the innate immune responses of human dendritic cells to bacterial and viral ligands.
520 $a In order to identify novel genes involved in the cytosolic DNA sensing pathway, we first identified candidate proteins that interact with known signaling molecules or with dsDNA in the cytoplasm. We then knocked down 809 proteomic, genomic, or domain-based candidates in a high-throughput siRNA screen and measured cytokine production after DNA stimulation. We identified ABCF1 as a critical protein that associates with DNA and the known DNA-sensing components, HMGB2 and IFI16. We also found that CDC37 regulates stability of the signaling molecule, TBK1, and that chemical inhibition of CDC37 as well as of several other pathway regulators (HSP90, PPP6C, PTPN1, and TBK1) potently modulates the innate immune response to DNA and to retroviral infection. These proteins represent potential therapeutics targets for infectious and autoimmune diseases that are associated with the cytosolic DNA response.
520 $a We also developed a high-throughput functional assay to assess variation in responses of human monocyte-derived dendritic cells to LPS (receptor: TLR4) or influenza (receptors: RIG-I and TLR3), with the goal to ultimately map genetic variants that influence expression levels of pathogen-responsive genes. We compared the variation in expression between the dendritic cells of 30 different individuals, and within paired samples from 9 of these individuals collected several months later. We found genes that have significant inter- vs. intra-individual variation in response to the stimuli, suggesting that there is a substantial genetic component underlying variation in these responses. Such variants may help to explain differences between individuals' risk for infectious, autoimmune, or other inflammatory diseases.
590 $a School code: 0084.
650 4 $a Health Sciences, Immunology. $3 1017716
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Systematic. $3 1676856
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710 2 $a Harvard University. $b Biology: Medical Sciences, Division of. $3 2097738
773 0 $t Dissertation Abstracts International $g 74-06B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3553439