tlr3 and amd
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TLR3 and AMDPeng ZHOU, M.D. Xiao-Xin LI, M.D.
Department of OphthalmologyEye and ENT Hospital of Fudan UniversityShanghai, P.R. China
April 8, 2023
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Toll-like Receptor 3 (TLR3)Pattern recognition receptors
of the innate immune system
Horseshoe shape
Recognizes double-stranded RNA (dsRNA)
induces the activation of NF-κB
and the production of type I interferons
Play a role in host defense against viruses
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
3
TLR3 and Dry AMD
TLR3 and Wet AMD
TLR3 and dsRNA
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
4
TLR3 and Dry AMD
TLR3 and Wet AMD
TLR3 and dsRNA
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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TLR3 and Dry AMD
V.S.
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
6TLR3 rs5743391 Protects Against Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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How to protect?
Step by step:
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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Plasmids
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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mRNA: RT-PCR
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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Protein: Western Blot
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
11Surface
expression:Flow cytometry
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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dsRNA Binding:REMSA
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
13NFkB:
Luciferase assays& EMSA
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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2012年眼底血管性疾病学习班及老年黄斑病变论坛
TLR3 rs5743391 = 50% TLR3
April 8, 2023
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2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
16
TLR3 and Dry AMD
TLR3 and Wet AMD
TLR3 and dsRNA
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
17
2012年眼底血管性疾病学习班及老年黄斑病变论坛
1. Kleinman ME et.al Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008 Apr 3;452(7187):591-72. Cole JE, et.al Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2372-7.
V.S.
TLR3 and Wet AMD?Theoretically…
1: Protect against CNV? 2. Risk Factor?
TLR3 rs5743391 =Risk Factor
TLR3 rs5743391 = 50% TLR3
V.S.TLR3 rs5743391 =
Protect against CNV
April 8, 2023
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TLR3 rs5743391 and Wet AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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TLR3 rs5743391 Protects against Wet AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
20
2012年眼底血管性疾病学习班及老年黄斑病变论坛
1. Kleinman ME et.al Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008 Apr 3;452(7187):591-72. Cole JE, et.al Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2372-7.
TLR3 and Wet AMDTheoretically…
1: Protect against CNV 2. Risk Factor
April 8, 2023
21Our Samples:
CNV-PCV-Control 95 : 92 : 95
g. - 855 A>G , Novel
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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In the near future:Needs more samples to confirm
new findings
Investigate the function of the above novel SNP and rs5743391
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
23
TLR3 and Dry AMD
TLR3 and Wet AMD
TLR3 and dsRNA
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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Where the dsRNAs come from?
G
1234CmRNA
Nuclei
412L
DNA
TLR3
NFkB
Dry AMD
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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Alu RNA?
Noncoding RNAs
Accumulation of Alu RNA transcripts in the RPE GA
Does Not Activate TLR3
2012年眼底血管性疾病学习班及老年黄斑病变论坛
1. Tarallo V, et.al DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88. Cell. 2012 May 11;149(4):847-592. Kaneko, H. et.al DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011.471, 325–330.uce
April 8, 2023
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Other dsRNA?
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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SummaryTLR3 rs5743391 protects against dry AMD
through decreased dsRNA binding capacity
TLR3 rs5743391 may protects against wet AMD
However, the mechanism needs further investigation
The resource of dsRNA needs further investigation
2012年眼底血管性疾病学习班及老年黄斑病变论坛
April 8, 2023
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Thank You!
2012年眼底血管性疾病学习班及老年黄斑病变论坛