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Neuro 4100: Basic and Clinical Foundations of Neurological Disease > 10/23: Glaucoma & Retinitis pigmentosa: > Flashcards

10/23: Glaucoma & Retinitis pigmentosa: Flashcards

1
Q

Glaucoma & Retinitis pigmentosa:

Animal models, cell replacement, neuronal survival and retinal regeneration

A

Andy Fischer

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2
Q

The 3 Diseases of the Retina discussed in this lecture:

A

glaucoma
AMD
retinitis pigmentosa

All of these involve the retina.

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3
Q

Significance and relevance:

A

The progressive loss of neurons from the retina underlies the loss of vision, and eventually blindness, that occurs in prevalent diseases such as macular degeneration, glaucoma and retinitis pigmentosa.

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4
Q

Sight-threatening diseases of the retina can be treated by:

A

Fixing what has gone wrong.

Promoting the survival of retinal neurons.

Replacing the lost neurons with new ones.

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5
Q

Request for input on the NEI RFI for the Audacious Goals

Initiative, as of October 2014

A

1) The current barriers to identifying and isolating appropriate stem cells for retinal transplants that will produce a sufficient number of functioning photoreceptors and/or retinal ganglion cells to restore visual function.

2) The current challenges to activating endogenous progenitor cells that will mature into a sufficient number of functioning photoreceptors or
retinal ganglion cells to restore visual function.

3) The barriers to overcome in guiding photoreceptors or retinal ganglion cells to make proper functional connections within the retina.
4) The current obstacles to triggering damaged or regenerated retinal ganglion cells to form new axonal projections with appropriate connections to central targets.

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6
Q

AMD stands for….

A

Age-Related Macular Degeneration

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7
Q

AMD is a disease of the ____ in the eye.

A

pigment cells

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8
Q

“Fixing what has gone wrong.”

A

Fixing the root issues of eye diseases is very complicated.

Many of these Diseases are Multigenic

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9
Q

“Promoting the survival of retinal neurons.”

A

Neuroprotective strategies.

This is the commonly used approach of the 3 approaches.

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10
Q

“Replacing the lost neurons with new ones.”

A

Providing new neurons that function in the place of dead/malfunctioning neurons.

Cell replacement and stimulating endogenous progenitor cells.

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11
Q

What kind of cell is the Muller cell?

A

Muller cells are glial cells that function as endogenous progenitor.

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12
Q

The ___ and the ___ refract light in the eye.

A

Cornea and lens

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13
Q

The retina is derived from the brain during development.

A

Thus, the retina is considered part of the nervous system.

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14
Q

sclera

A

connective tissue in the eye that provides structural support.

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15
Q

Rods

A

Function best in low levels of light

Don’t discern color.

VERY sensitive to light.

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16
Q

Cones

A

Daytime Vision, High visual acuity.

Color vision

3 different types of cone photoreceptors for detecting red, green, and blue light.

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17
Q

Muller Glia:

Basics

A

Support Cells that function similarly to astrocytes.

Structural, Synaptic, and Metabolic Support.

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18
Q

Age-related Macular Degeneration

A

AMD
Results in loss of central (macular) vision

Age-related macular degeneration is a disorder of the retinal pigmented epithelium.

AMD is initially identified as a build-up drusen deposited by
malfunctioning RPE cells

When neo-vascularization occurs with AMD — things go from bad to worse.

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19
Q

Macula

A

central region of the retina

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20
Q

There are 2 different types of macular degeneration:

A

Wet and Dry

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21
Q

Wet Macular Degeneration

A

Involves neovascularization (formation of new blood vessels).

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22
Q

Dry Macular Degeneration

A

build-up drusen deposits

Drusen is the white spots.
They prevent nutrient exchange.

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23
Q

We don’t gain retinal cells.

A

The ones you are born with are all you have til you die, for the most part.

24
Q

Photoreceptors are very metabolically active.

A

For this reason, they experience a lot of oxidative stress.

25
Q

AMD research

A

stem cells lookretinal pigmented epithelial cells being added/activated, since AMD occurs when RPEs arent properly cleaning up the metabolic waste of the photoreceptors.
very promising in restoring vision

26
Q

Multiple genes can make you predisposed to macular degeneration.

A

….

27
Q

macular degeneration and neo-vascularization

A

When neo-vascularization occurs with AMD — things go from bad to worse.

28
Q

retinitis pigmentosa

A

Invasion of pigmented cells into peripheral retina

29
Q

What causes retinitis pigmentosa?

A

Hundreds of mutations in >50 different genes that are normally expressed by rods can result in rod-degeneration and RP

Rods degenerate, then cones degenerate, then pigmented cells invade the retina

The inner retinal neurons can remodel connections after the
photoreceptors have been lost, otherwise the inner retinal is not too messed-up.

30
Q

Glaucoma:

A

characterized by elevated intraocular pressure and loss of visual acuity in the periphery

Overproduction of vitreous fluid of an inability to clear it.

31
Q

Optic Nerve in Glaucoma

A

Optic Nerve head cups-in due to pressure, constricts on ganglion axons (particularly the peripheral axons), and kills ganglion cells.

This makes the optic nerve less thick because it has lost axons…

Eventually, this results in loss of the Peripheral vision.

32
Q

Does the Muller cell behave more like a stem cell or a glial cell in a normal, healthy eye?

A

Muller cell usually behave as glial cells, their normal funtions are suppotive glial roles.

But, you can stimulate a stem cell to act like a progenitor stem cell.

33
Q

Getting ESCs and iPSCs to do the right thing is a little complicated:

A

Different culture conditions promote the production of particular types of neurons from ESCs

34
Q

Biggest hurdles to replacing retinal ganglion cells (RGCs) in
retinas ravaged by glaucoma:

A

(1) Getting precursor cells to differentiate properly into RGCs
(2) Getting the host tissue and immune cells to accept and support the donor cells
(3) Getting the transplanted RGCs to integrate properly into the host retina (i.e. make connection in the inner plexiform layer, and become an appropriate type of RGC)

(4) Getting the transplanted RGCs to form an axon that projects to the optic nerve , through the optic chiasm and make appropriate connections in higher visual center (lateral geniculate nucleus).
All the factors that help this happen are only transiently present during development, which makes this challenging to use these methods in an adult.

35
Q

Stem cell therapies:

A

Transplanting neural or retinal stem cells to repair diseased retinas

Good idea? NO

Pubmed search “naive retina stem cell transplantation”
= >500 papers since 2000.

Number of papers with convincing examples of functional cell replacement from transplanted naïve neural/retinal stem cell = 0

The cues to guide a naive stem cell to repair the retina are not present in adults.

36
Q

Some progress has been
made in transplanting
photoreceptors
precursors

A

The key is to wait until the stem cell is just about ready to differentiate into the desired final product before putting it in the eye; completely naive stem cells fail.

  • Transplant about 500,000 cells and get about 300 integrated photoreceptors
  • Functional Restoration of vision after transplantation of
    photoreceptors
  • Cone & rod photoreceptor transplantation in models of the childhood retinopathy Leber congenital amaurosis using flow-sorted Crx-positive donor cells
37
Q

Biggest hurdles to replacing photoreceptor cells in retinas ravaged by AMD or retinitis pigmentosa:

A

(1) Getting precursor cells to differentiate properly into cone photoreceptors.
(2) Getting the host tissue and immune cells to accept and support the donor cells
(3) Getting the transplanted photoreceptors to integrate properly into the host retina (i.e. make connection in the outer plexiform layer)

38
Q

Are there retinal stem cells in an adult eye?

A

NO

39
Q

What about a retina-intrinsic cellular source for regeneration?

A

….Muller glia??

In fish cells, muller glia are true stem cells that readily repair on their own
But this ability goes down as you go up the evolutionary scale.

40
Q

What do Muller glia do?

A

Structural support, metabolic support, synaptic support, light-guides, etc…

41
Q

Key questions in the field of retinal regeneration:

A

Why do Müller glia in the zebrafish do a fantastic job regenerating retinal neurons, whereas the Müller glia in chick and rodent retina do a crappy job?

What signals influence the formation of Müller glia-derived progenitors cells?

What signals influence the neuronal differentiation of the progeny of Müller glia-derived progenitors cells?

Can Müller glia be stimulated to become neurogenic without
damaging the retina first?

42
Q

How do Müller glia become retinal progenitors?

A

Factors to stimulate proliferation

Factors to stimulate differentiation

Signals to stimulate De-differentiation

Expression of factors to stimulate MGs to become more progenitor-like (Sox2, KLF4, etc…)

43
Q

The signaling pathways and transcription factors involved in turning Muller
glia into retinal progenitors is complicated

A

……

Using damage to stimulate growth factors… Finding new ways to stimulate repair without damaging

44
Q

Inhibition of the FGF-receptor and MAPK signaling prevents the formation of MGPCs in damaged retinas.

A

Inhibition of the FGF-receptor and MAPK signaling prevents the formation of MGPCs in damaged retinas.

45
Q

Is FGF2 alone sufficient to induce the formation of MGPCs?

With no damage?

A

FGF2 selectively activates MAPK-signaling in Muller glia.

46
Q

Reactive microglia (immune cells) are prevalent in all models of retinal regeneration involving damage or injections of growth factors…

A

…in fact, merely puncturing the eye appears to “annoy”

microglia and create a damage response, even without damage.

47
Q

Perhaps reactive microglia influence the ability of Muller glia to become proliferating
MGPCs?

A

But in the absence of microglia, the muller glia don’t become progenetor-like.

48
Q

With the microglia ablated, and most of NIRG cells gone, numbers of
proliferating MGPCs significantly reduced in damage retinas.

A 
FGF2 fails to 
stimulate the 
formation of 
MGPCs when the 
microglia have 
been ablated.
49
Q

Summary of Muller Glia and the Research

A

(1) Muller glia have the potential to be a retina-intrinsic source of neuronal regeneration.
(2) Muller glia can be stimulated by retinal damage or FGF2/MAPK signaling to become proliferating progenitor cells that are capable of producing new neurons.
(3) FGF2/MAPK-signaling initiates a network of signaling pathways the influence the formation of MGPCs.
(4) The network of signaling pathways involves mTor, GCR and unidentified signals from reactive microglia, and pathways not discussed such as Notch, Wnt, Jak/Stat3, HB-EGF

50
Q

Light-Sensitive Cells

A

Photoreceptors

51
Q

Induced Pleuripotent Stem Cell

A

Reprogrammed Cell

52
Q

FGF

A

Very Good NeuroProtectant

FGF signaling —> Snowballing

53
Q

Inducing Damage

A

Inducing damage has been the primary method for treatment because it causes Muller glia to respond as stem cells, but new treatments are being developed.

54
Q

Microglia…

A

Reactive Microglia are involved in proper differentiation.

55
Q

fundiscope

A

used to assess macular vision

Neuro 4100: Basic and Clinical Foundations of Neurological Disease (18 decks)

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