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Repair And Regeneration > Week 8 Part 2 > Flashcards

Week 8 Part 2 Flashcards

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1
Q

What is Retrograde signalling of cytokines to sensory neurons (A)

A

After injury, CNTF is released from Schwann cells, LIF synthesis is induced in Schwann cells
IL-6 synthesis is induced in neurons
IL-1 and tumour necrosis factor alpha released at site of injury

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2
Q

Retrograde signalling (B)

A

CNTF, LIF and IL-6 activate the gp130 receptor which recruits Janus kinases to phosphorylation STAT3. pSTAT3 dimerises and be imported into the nucleus

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3
Q

Retrograde signalling (C)

A

STAT3 dimers bind directly to specific sequences in DNA

Induce transcription of many genes related to inflammation and repair

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4
Q

What are other molecules released by Schwann cells?

A

Other cytokines
Growth factors
Enzymes
Chemokines

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5
Q

Other cytokines

A

IL-1alpha, IL-1beta, TNF alpha (tumour necrosis factor alpha)

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6
Q

Growth factors

A 
GDNF
NGF
BDNF
NT-3
TGF-beta
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7
Q

Enzymes

A

Metalloproteinase 9 (MMP9)

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8
Q

Chemokines

A

MCP-1
CCL2
CCL3

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9
Q

What 2 molecules are used for axon regeneration?

A

GAP-43

SPR1A

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10
Q

What does macrophages and Schwann cells produce?

A

Matrix metalloproteases that interrupt the blood-nerve barrier

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11
Q

What is released when the blood-nerve barrier is interrupted?

A

CGRP
Substance P
Bradykinin
Nitric oxide

  • induct hyperaemia and swelling - promote the invasion of further monocytes and T lymphocytes
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12
Q

What is the role of CCL2 and CCL3?

A

Attract and guide monocytes to the lesion site

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13
Q

What is the role of macrophages and mast cells?

A

Release prostaglandin and cytokines

IL-1B, IL-6, IL-18, TNF and LIF

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14
Q

What does blood vessels have?

A

MCP-1

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15
Q

What do cells at injury site release?

A

Variety of cytokines

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16
Q

What does IL-10 from macrophages inhibit?

A

Fibroblasts and Schwann cells

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17
Q

What happens after nerve injury?

A

Expression of thousand of genes changes

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18
Q

What are regeneration associated transcription factors?

A

STAT3, ATF3, cJun, CREB, SOX11, SMAD1, KLF7, C/EBPdelta, p53

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19
Q

What are terminal RAGS?

A 
GAP43
CAP23
Galanin 
PACAP
Rac1
Cdc42
Arginase I
CRMP2
GDNF
BDNF
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20
Q

What does ATP released after injury trigger?

A

Neural responses to an injury

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21
Q

What does ATP release cause?

A

Peripheral cells to release cytokines

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22
Q

What is Calpain?

A

An intercellular Ca2+ dependent cysteine protease

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23
Q

How do neuronal bodies sense injury?

A

Rapid phase

Slow phase

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24
Q

Rapid phase

A

Injury-induced discharge of axonal potential and ions

Goes back to cell body

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25
Slow phase
Conveyed by molecular motors
26
What is negative injury signals?
Interruption of normal supply of retrogradely transported trophic factors of negative regulators of neuronal growth from target
27
What is positive injury signals?
Retrograde transport of activated proteins at injury site
28
What does calcium wave lead to?
Molecular changes in the neuronal soma
29
What does sudden calcium change result in?
Body detecting there’s an injury
30
What is one of the molecules involved with calcium waves?
Histone deacetylase 5 with protein kinase
31
What does epigenetic change result in?
Histone acetylation
32
What does nuclear export of Histone deacetylase via protein kinase enhance?
Histone acetylation | Priming the chromatin for subsequent transcription events
33
What is a big player in peripheral axon regeneration?
Neurgulin
34
What does Neuregulin do?
Bind to receptor ERBB2 which is on the Schwann cells | It is released in the axons
35
What does axons have ?
TRKA receptors
36
What molecules are early injury signals?
``` IL-6 family Gp130 family Neuropoietic family Interleukin-6, IL-11, IL-27 Ciliary neurotrophic factor (CNTF) Leukaemia inhibitory factor (LIF) Cardiotrophin 1 (CT-1) Neuropoietin Cardiotrophin-like cytokines (CLC) ```
37
What does Neuropoietic cytokines activate?
JAK-STAT and MAPK pathway
38
What are signalling pathways of neuropoietic cytokines?
Jak STAT3 SOCS
39
Jak
Janus-family tyrosine kinases
40
STAT3
Signal transducers and activators of transcription 3
41
SOCS
Suppressor of cytokine signalling
42
Where is CNTF highly expressed?
Schwann cells | Has no signal peptide - not secreted by conventional pathways
43
What is experimental evidence of earl injury signal?
1. Phosphorylation and nuclear translocation of STAT3 was maximally induced within 12h post lesion in motoneurons of facial nucleus of wild type mice - maintained for 3 days 2. In CNTF-deficient mouse, activation of STAT3 signalling was delayed by 10-12h 3. Application of CNTF to transects nerve restored STAT3 activation in CNTF- deficient animals
44
Why is LIF important?
Increases the regeneration state of injured neurons
45
What are other transcription factors involved in injury induced responses?
ATF3
46
ATF3
Injury marker Regeneration marker Pain marker
47
What does the gene GAP-43 show?
Undergo axon growth
48
What gets travelled all the way up to the injury site because the gene is made in the cell body?
GAP-43 and CAP23
49
What does two sequential injections of ATP significantly promote?
Sensory axon regeneration in spinal cord
50
What are demyelination pathways?
JIP | Calpain
51
What is JIP?
JNK-interacting protein of scaffold protein | Mediate JNK signaling by aggregating specific components of MAPK cafe to form functional JNK signaling module
52
What is calpain?
Intracellular Ca2+ dependent cysteine protease
53
What gene is involved in WLDs?
NMNAT1
54
Where is NMNAT1 located?
Nuclei Also expressed in axonal cytoplasm Organelle: mitochondria
55
What are factors controlling early Schwann cell development and myelination?
``` NRG1 B1 integrity’s Claw paw Laminin P75 NTR TGF beta BRN2 Krox20/ NAB 1/2 NRG1 OCT6 ```
56
What does different types of neuregulin carry?
Epidermal growth factor (EGF) domain | 5 matured forms are soluble
57
What is matured type III ?
Membrane bound protein | Interact with receptors in Schwann cells
58
What is ErbB proteins?
Type 1 transmembrane receptor tyrosine kinase
59
What does Neuregulin 1 (NRG1) stimulate?
ErbB to dimerize
60
What does ERB2 have?
Active kinase domain
61
ErbB3
Binds to NRG1 but has an impaired tyrosine kinase domain
62
ErbB4
Homodimers can bind to NRG1 and become activated
63
What does NRG-III tell Schwann cells?
Myelinate axons
64
What does injury have?
Growth cone | For axons to grow back again it needs to have growth cone
65
What does growth cones have?
Microtubules which go all the way back to the cell body Have actin surrounding Fingers Filopodia
66
What does P domain contain?
Unipolar actin filament bundles embedded in a less polar actin network Contains: lamellipodia and filopodia
67
What is T domain?
Thin interface between P and C domain
68
Where is C domain located?
Centre of growth cone nearest the axon | Composed of microtubules and contains numerous organelles and vesicles
69
What does membrane rupture lead to?
Elevation of the free intra-axonal ca2+
70
What are the process of axon growth?
Protrusion Engorgement Consolidation
71
What is protrusion?
Rapid extension of filopodia and thIn lamellar protrusion | extension are primarily composed of bundled and mesh-like F-actin networks
72
What is Engorgement?
Microtubules invade protrusion bringing membranous vesicles and organelles
73
What is consolidation?
F-actin depolymerises in the neck of growth cone and membrane to shrink around the bundle of microtubules to form a cylindrical axon shaft
74
What does calcium wave lead to?
Molecular changes in the neuronal soma
75
What is calcium wave?
Sudden change in calcium that results in cell body detecting there’s injury
76
What is one molecule that’s involved in calcium wave?
Histone deacetylase 5 with protein kinase Cm
77
What does epigenetic change result in?
Histone acetylation
78
What does nuclear export of Histone deacetylase 5 via protein kinase activation lead to?
Enhancing Histone acetylation | Pruning the chromatin for subsequent transcription events
79
Molecular changes in the neuronal soma?
Calcium ion flux into the axons Released from internal stores Generate calcium waves Spread to soma and trigger gene expression
80
What happens when there is damage to the axons?
Schwann cell axon interaction
81
What is a key player in peripheral axon regeneration?
Neuregulin
82
What is the role of Neuregulin?
Bind to its receptor ERBB2 (on Schwann cells) | Released in axons when injured
83
What does axons have?
TRKA receptors
84
What molecules are early injury signals?
``` IL-6 family Gp130 family Neuropoietic family IL-6, IL-11 and IL-27 Ciliary neurotrophic factor (CNTF) Leukaemia inhibitory factor (LIF) Cardiotrophin 1 (CT-1) Neuropoietin Cardiotrophin-like cytokine (CLC) ```
85
Signalling pathways of neuropoietic cytokines
Shown through IL-6 receptor JAK: Janus-family tyrosine kinases STAT3: signal transducers and activators of transcription 3 SOCS: suppressor of cytokine signalling
86
What is another pathway for regeneration?
PI3 kinase AKT pathway
87
What is CNTF?
Early injury signal Highly expressed in adult Schwann cells Has no signal peptide - not secreted by conventional pathways Can be released instantly after Schwann cell damage
88
What is experimental evidence for CNTF?
1. Phosphorylation and nuclear translocation of STAT3 was maximally induces within 12h post lesion in motoneurons of facial nucleus of WT mice and maintained for at least 3 days 2. In CNTF- deficient mouse, activation of STAT3 signalling was delayed by 10-12h
89
What is CNTF neuroprotective for?
Motoneurons Sensory neurons Retinal ganglion neurons
90
Where is LIF mRNA levels increased?
Both proximal and distal stumps soon after PNI
91
What is LIF important for?
Increasing the regeneration state of injured neurons
92
What is bi-directional relationship between axons and Schwann cells during neural repair?
1. Axons are re-myelinated 2. Schwann cell begin re-myelination 3. Schwann cells ensheath the axons 4. As Schwann cells re-contact axons they proliferate

Repair And Regeneration (16 decks)

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