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Increased inflammatory responses in ...

Weill Medical College of Cornell University.

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Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection./
Author:	Yin, Fangfang.
Description:	141 p.
Notes:	Adviser: Aihao Ding.
Contained By:	Dissertation Abstracts International69-11B.
Subject:	Biology, Neuroscience. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3335297
ISBN:	9780549888079

Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection.
Yin, Fangfang.

Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection. - 141 p.

Adviser: Aihao Ding.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2008.

Progranulin (PGRN) is a secreted pluripotent glycoprotein, whose loss-of-function mutations were found in patients with frontotemporal dementia (FTD). The mechanisms by which PGRN deficiency leads to FTD are currently unknown. Our group previously showed that PGRN acts as an anti-inflammatory molecule by suppressing neutrophil activation and promoting wound healing in mice lacking secretory leukocyte protease inhibitor (SLPI). It is not known whether PGRN's regulatory functions in inflammation contribute to neuronal survival.

ISBN: 9780549888079Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection.
LDR:03543nam 2200313 a 45 001 855239
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020 $a 9780549888079
035 $a (UMI)AAI3335297
035 $a AAI3335297
040 $a UMI $c UMI
100 1 $a Yin, Fangfang. $3 1021794
245 1 0 $a Increased inflammatory responses in progranulin knockout mice: Implications for neurodegeneration and infection.
300 $a 141 p.
500 $a Adviser: Aihao Ding.
500 $a Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6687.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2008.
520 $a Progranulin (PGRN) is a secreted pluripotent glycoprotein, whose loss-of-function mutations were found in patients with frontotemporal dementia (FTD). The mechanisms by which PGRN deficiency leads to FTD are currently unknown. Our group previously showed that PGRN acts as an anti-inflammatory molecule by suppressing neutrophil activation and promoting wound healing in mice lacking secretory leukocyte protease inhibitor (SLPI). It is not known whether PGRN's regulatory functions in inflammation contribute to neuronal survival.
520 $a In an attempt to address the questions above, we generated PGRN conditional knockout (PGRN-/-) mice including ubiquitous (CAG-), myeloid (LysM-) and neuronal (Nestin-) PGRN-/- mice using the Cre-LoxP system. These mice bred normally, and did not show any gross phenotypic abnormalities. However, when we treated primary bone marrow-derived macrophages (BMDMs) with lipopolysacchride (LPS), PGRN-/- cells responded by secreting increased amounts of pro-inflammatory cytokines/chemokines such as MCP-1, TNF-alpha, IL-6 and IL-12p40, but reduced amounts of the anti-inflammatory molecule IL-10, as compared to wild-type (WT) controls. The dys-regulated inflammatory responses of PGRN-/- macrophages rendered CAG-PGRN -/- mice more susceptible to infection with Listeria monocytogenes than WT mice. CAG-PGRN-/- mice developed meningoencephalitis with inflammatory cells infiltrating the ventral meninges, while infected WT mice did not.
520 $a PGRN is expressed by microglia and neurons in the brain. We found that exposure of hippocampal slices from CAG-PGRN-/- mice, but not from Nestin-PGRN-/- mice, to oxygen and glucose starvation led to more neuronal damage than those from WT controls, suggesting a role for microglial cells in the neuronal fate. Addition of (LPS+IFNgamma)-stimulated PGRN-/- BMDMs caused more cell death in the hippocampal slices than WT BMDMs. In the absence of added BMDMs, (LPS+IFNgamma)-stimulated endogenous microglial cells from CAG-PGRN-/- mice also induced more cell death in the hippocampal slices than those from WT mice.
520 $a Taken together, these results suggest that deficiency of the pgrn gene directly affects macrophage innate responses, resulting in inflammatory imbalances in the defective host, which may in part contribute to the detrimental effects on neurons as seen in FTD patients. Three conditional PGRN knockout mouse colonies, generated in this study, should provide excellent models for elucidating mechanisms underlying PGRN-related diseases and aid in the development of therapeutic strategies.
590 $a School code: 0967.
650 4 $a Biology, Neuroscience. $3 1017680
650 4 $a Health Sciences, Immunology. $3 1017716
690 $a 0317
690 $a 0982
710 2 $a Weill Medical College of Cornell University. $3 1021736
773 0 $t Dissertation Abstracts International $g 69-11B.
790 $a 0967
790 1 0 $a Ding, Aihao, $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3335297