Regen Final 568

Front 1

What are the Neuroprotective Agents? (9)
My Good Neighbor Pablo Can 4 C Cunts Rising

Back 1

1. Methylprednisolone
2. Gacyclidine
3. P2X7R antagonists
4. Carboxy buckyballs
5. 4-Aminopyridine
6. Carbamylated EPO
7. cAMP
8. NMDA
9. Rolipram

Front 2

What Neuroprotective agents eventually Have to do w/Ca?

Back 2

Gacyclidne
NMDA
P2X7R antagonists
cAMP
Rolipram

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Methyprednisolone

Back 3

Neuroprotective Agent: Steroid

Stabilizes Cell membranes

Front 4

Gacyclidine

Back 4

Neuroprotective Agent

NMDA Antagonist --> Inhibits Ca influx

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NMDA

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Neuroprotective Agent
Glu receptor

--> Inhibits Ca influx

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P2X7R antagonists

Back 6

neuroprotective agents: OXATP, PPADS

inhibits Ca influx by antagonizing P2X7R (ATP receptor)

Can't cross Bl. Brain Barrier, but Brilliant Blue G can--> rats w/Spinal injuries have reduced inflammation, better stepping motion, & bladder control

Front 7

Carboxy Buckyballs

Back 7

Neuroprotective Agent

neutralizes free radicals

Front 8

4-Aminopyridine

Back 8

Neuroprotective Agent

Improve Conduction in spared demyelinated axons by opening K+ channels

Front 9

Carbamylated EPO

Back 9

Neuroprotective Agent

Reduces Inflammation via Unknown receptor

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cAMP

Back 10

Neuroprotective Agent

Restores normal Ca balance by closing Ca channels

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Rolipram

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Neuroprotective Agent

Resortes normal Ca balance by degrading PDE 4

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how are cAMP, PDE, & Ca linked in neurons?

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cAMP closes Ca channels, restoring normal Ca balance

Injured axons have high Ca --> upregulates PDE, which breaks down cAMP & stops cAMP from closing Ca channels, leading to Toxic intracellular Ca levels

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Rho A in neurons

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Rho A: small GTPase
bound to GTP Rho A depolymerizes actin cytoskeleton (growthcone)

NoGO, MAG, Ompg all signal through NoGo Receptor --> Activating Rho A

Front 14

these are ligands for the NoGo Receptor

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Cause GC collapse
NoGo
MAG
Ompg

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soluble molecules that inhibit Rho A pathway --> inhibits Growth Cone collapse (9)

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BDNF, GDNF, NGF, NT-3
NoGo 66
NoGo Ab + injection of NTF-3
Bac C3 transferase
Inhibitors of Rho Kinase

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myelin Ab

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Promotes Axon elongation

Inhibits GC collapse

Front 17

What are the targets for agents that promote axon elongation & NSC survival

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inhibit Rho A pathway
inhibit EGFR kinase activity (internal domain)
Myelin inhibitory proteins

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Agents that limit Glial Scar

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Minocycline

CM101

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Minocycline

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Agent that limits Glial Scar: (Antibiotic)

limit cavitation & glial scar by targeting Inflammatory Cells

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CM101

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Agent that limits Glial Scar: (polysccharide from Stretococcus B)

limit glial scar by targeting Inflammatory cells

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Agents that allow traverse or bypass Glial Scar

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Chondroitinase ABC
Fetal Spinal Cord (into newborn rats)
Intercostal nerves in FGF-1 loaded fibrin matrix
Collagen 1 + Ln or 4-Aminopyridine

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Chondroitinase ABC

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Agent that allow traverse or bypass of glial scar

Targets CS-GAGs of PGs
-->increases adhesivity of scar suface

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Fetal Spinal Cord into newborn rats

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Agents that allow traverse or Bypass of the Glial Scar

Promotes axon elongation via adhesion molecules & soluble factors
Targets Axon surfaces

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Intercostal nerves in FGF-1 loaded fibrin matrix

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allows tranverse or bypass of glial scar

Mice not people
use axon tubes --> adhesive guidance of axons
Targets: axon surfaces

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Collagen 1 + Ln or 4-axons

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Adhesive guidance of Axon Surfaces

Targets aminopyridine
Cat

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Cell transplants

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Schwann cells (2)
OECs (Olfactory Ensheathing Cells)
Splenic dendritic cells
Cord Blood
Fibroblasts

Front 27

Ways that Topical Agents are used for Acute wounds

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Enhance Hemostasis
Reduce Inflammation
Enhance structural repair

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Acute Wound: Enhance Hemostasis

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QuikClot

Hem Con Bandage

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QuickClot

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Over the Counter
hydrous aluminum silicate (zeolite) & Ca++
Absorbs water FAST < min

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Hem Conn Bandage

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Enhance hemostasis
chitosan (+)
pulls neg charged RBCs into bandage --> tight fitting plug over wound

Front 31

3 ways of Reducing Inflammation in Acute wounds

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Debriding agents
Antibacterials
Anti-inflammatories (anti scarring)

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Debriding agents

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Vibrolysin
Papain/urea
Medical Maggots

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Vibriolysin

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Debriding Agent: Reduces Inflammation

Enzyme

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Papain/urea

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Debriding agent: Reduces Inflammation

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Medical Maggots

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Debriding Agent: Reduces Inflammation

green blowfly (Phaenicia sericata)
liquefy necrotic tissue
antibiotic
amps helaing of EGF & IL-6

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Acute Wound
Reduce Inflammation: Antibacterials

Back 36

oleic n-9 FA
HB-107 cecropin B peptide
honey

Front 37

Topical Agents for Re-Epithelialization of Acute Wounds

Back 37

HA/CS hydrogel

Epiregulin (thicker epidermis)

Front 38

Topical Agents for Angiogenesis of Acute Wounds

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Fentanyl (Narcotic, colonoscopy)
Pig Enamel matrix
Ketanserin (blocks serotonin R-hypertension)
Angiotensin (proliferates endo)
VEGF (proliferates endo)

Front 39

Topical Agents for FB migration/proliferation of Acute Wounds

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Extract of C. agentia (cockscomb/quail grass)
NA/CS hydrogel
EGF
FGF-2
TGF Beta 1,2
hGH
Vanadate (more collagen-thicker)
Oxandrolone (Anabolic Steroid --> mature & dense collagen

Front 40

Regen Templates for Acute Wounds

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Alloderm
Integra
DeVries

Front 41

Alloderm

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Scafold for Acute Wound
Human Dermal Matrix
works best if
+ keratinocytes
+ Meshed Split Thick Skin Grapht MSTSG

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ESC need this factor to proliferate in an undifferentiated state

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Mouse: LIF

Human: FGF-2

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Directs ESC to become Neurons

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Retinoic Acid

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Who ASC --> ESC

Back 44

Takahasahi et al 2007 (Sinya Yamanka)

Yu et al 2007 (James Thompson)

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Sinya Yamanka TF

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Oct4
Sox2
Klf4 (cell division)
c-Myc (cell division)

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James Thompson TF

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Oct4
Sox2
Lin28
Nanog

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What TF are found in blastem & used for iPSC

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Sox2
Lin28
Nanog
Klf

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problems w/iPSC

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1. direct differentiation not fully understood (100%) Teratomas
2. how robust? Last how long?
3. Function
4. Cost - testing for Efficacy & Safty
5. Feasibility --> Rejuvination/Ethics

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Goals of Chemical Induction

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1. Enhance repair by scar tissue
2. Stimulate Cell growth (axons)
3. Stimulate resident ASC
4. Dedifferentiation --> ASC
5. transdifferentiation
6. Compensatory Hyperplasia

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Integra

Back 50

Acute Scaffold
Bovine Col1 + Chondrotin 6 sulfate
Clinical use for burns

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DeVires

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Acute Scaffold
Collagen + elastin
Netherlands 1994
Not in US yet

Front 52

Why don't cell transplants work for Acute wounds (burns)

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damaged dermis can't produce GF needed for epidermis

Front 53

Bioartificial Skin Equivalents

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living wound dressings
scaffold + keratinocytes (allogeneic --> rejected)
allows skin to heal

Front 54

Re-Epithelialization for Chronic

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KGF-2 (Repifermin)
Beta-NGF
PDGF-BB; better/w TGF-alpha

Front 55

What neurprotective agents inhibit Glu's action --> Ca influx

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NMDA
Gacyclidine

Front 56

Neuroprotective Agent that's an ATP receptor Antagonist

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OXATP
PPADS

(P2XR7)

Front 57

prevent GDP --> GTP on Rho A

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BDNF
GDNF
NGF
NT-3

Front 58

inhibits NoGo R by binding to it

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NoGo66

Front 59

inhibits end result of RhoA pathway

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Inhibitors of Rho Kinase (ROCK)

Front 60

how is the Glial scar limited?

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targeting inflammatory cells

Minocycline (Antibiotic)
CM101 (Strep B polysac

Front 61

cell transplant that produced partial recovery from SCI

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OEC
APC

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Cell transplant for SCI that produce paracrine & Juxtacrine

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APC
Splenic dedritic cells (Rat)

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APC
in vivo
in vitro

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vivo: paracrine, NSC --> partial functional recovery

vitro:dendritic cells --> Juxacrine --> NSC survival & proliferation

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Androgenetic Alopecia

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test --> 5 alpha reductase --> DHT
Telogen (rest) elongates
Anagen (grow) shortens
Catagen (destroy) same

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Androgenetic Alopecia: topical treatments

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Rogaine (minoxidil)
Propecia (finasteride)

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Rogaine (minoxidil)

Back 66

--> minoxidil sulfate
K+ channels
slows hair loss, but don't regrow

Front 67

Propecia (finasteride)

Back 67

blocks 5-alpha reductase
restores anagen length

Front 68

Future Androgenetic Alopecia

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inject bulge & Dermal papilla
--> dermal papilla Wnt restores anagen

Front 69

Most prevalent Neurodegen Disease

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Multiple Sclerosis

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MS

Back 70

T cells attack myelin
Autoimmune, demyelinating disorder
Can lead to sensory, motor, cognitive Defects

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Alzheimer's Disease

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Beta Amyloid aggregation
tau protein
Hippocampal degeneration
intrafiliment inhbits synapses

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Huntington's Disease

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loss of Multi striatal neurons
b/c repeats of Glu (CAG-CAG-CAG)
--> can't move BDGF

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ALS stands for

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Amyotrophic: lack of muscle nourishment
Lateral : location of motor columns in spinal cord
Sclerosis: scaring (motor neuron death)

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ALS: types

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Sporadic - 90%
Familial - 10%; of which 20% mutated SOD-1

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ALS molecular abnormalities

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Neurofiliment bulidup in motor neurons
low retinoid pathway enzymes
high Glu in CSF b/c astrocytes downreg GLT1 --> influx Ca

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G93A mouse model

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mouse model of ALS
SOD1 mutant (not 95% of cases)
2O2- + 2 H2O --> O2 + H2O2 + 2 OH—

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G93A Culture Experiment

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cultured w/WT neurons --> 1/2 Apop
Paracrine Factors
- Inflammation b/c Prostaglandins --> NOS ->

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G93A secretions

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Upped Prostaglandins --> Upregulated Prostaglandins --> NOS1 (nitric oxide synthase) --> NOX2

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ALS research Q's

Back 79

1. what initiates

2. Progression: Astro toxic to Motor N ?
3. same Initation & progression in familial & Sporadic?

iPSC- any good- Epigenetic;
- Compare Familial & sporadic
- screen for initiating factors

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ALS: have tried the following factors

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delayed initiation
- siRNAs for G93A
- IGF-1, FGF, CNTF, VEGF
- Caspase inhibitors (Cas --> Apop
- COX2 inhibitors (b/c inflammation
- Antibiotics (increase Glu1

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bioartifical pancrease

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Cadaver Islet cells mixed into Alginate
spread over CaPO4 --> cross links Alginate
microsphere w/pores

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Bioartifical Chin

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Ti Cage + MSC
- BMP7 (drives MSC into osteoblasts)
- Bovine Bone Matrix (accelerates process)

Made pocket underskin to get it vascularized (Body as a bioreactor)

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Bioartifical Bladder

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polyester matrix seeded w/
- epithelial, fibroblasts, smooth muscle

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Esophagus (Tracea)
Had TB

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Decellularized
autogenetic MSC --> Fibro, Chondro, & muscle

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Bioartifical Bone

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frogs
MSC + BMP4 --> Chondrocytes
vascular

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Satellite --> MI heart

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increased LVEF 8-9% 6months
Augment Contraction
Paracrine factors that
-cardiomyocyte survival
- Promoting angeiogenesis
- Inhibiting scar formation

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Fetal Cardiomyocytes

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dog, pig
differentiated but remained immature

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Cardiac SC --> Rat

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Regen: 31% decrease infarct size
but remained immature

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BM into MI

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Wollert 2004
6.7% increase LVEF
= 42% improvement

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G-CSF + BM
Granulocyte colony stimulating factor

Back 90

Zohlnhofer et al (2006)
G-CSF upped HSC
6.2% decrease Infarct
.5% increase LVEF (less than placebo)

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MSC transfected w/Akt

Back 91

Mangi (2003)
Akt gene --> Protein Kinase B- inhibits Apop

LVEF --> Norm
Healed Infarct

--> MSC NO diff into Cardio
--> b/c more paracrine factors, upped Cardio survival & angiogenesis, dropped fibrosis

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Akt cardiomyocytes under hypoxic

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Gnecchi (2005) Thymosin B-4 (TB4)
regular Cardio Apop
Akt Cardio 41% survived
Media --> MI upped survival 60%, Infarct droped 40%

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Thymosin B-4 (TB4)

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binds actin monomers
TB4 is upped after MI
--> Activated (P-late) Akt
--> Expands heart tissue

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TB4 expands Heart tissue

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TB4 caused migration EndoCardial --> MyoCardium

(AcSDKP) TB4 self cleaved tetrapeptide that caused differentiation into Sm muscle & endothelium

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TB4 --> MI mouse

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reduced Apop, Scarring, & upped Angio
LVEF 21--> 44, but Norm=75

Front 96

HSC transplant Experiment
Donor: P-CRE-GFP
Host irradiated ROSA26: Promoter-FSC-LaxZ(reporter)

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FSC: Flox Stocked Cassette- LoxP removes FSC, FSC protects LaxZ
GFP in blood, Beta-gal found b/c fusion in Hepatocytes, Cerebellum, Heart

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Fussion naturally occurs in

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Osteocyte
Muscle
Zygote

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HSC 2
Donor: Promotor-FSC-GFP, male (Y)
Host: leathally irradiated, P- CRE

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found Y+ cells lung, liver, wounded Epidermis
No GFP --> no Fussion

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Old Don't heal well

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less Delta expression (maintains Notch intracellular signaling)

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Old Cells in young serum

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upped Delta --> Notch --> SC proliferation

Young in old was opposite

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Cenegenics

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MGF & Growth Hormone w/strength training can retard loss of muscle due to aging

GH & train increases endogenous MGF