Download 22- Sesion 5 - Noel Garcia Speaking

Failures in Epithelial Social Networks
lead to Pathology and Aging
NoelGarcíaMedel,PhD
2017,May26th
1.Epithelia:StructureandFunction
Epitheliaisolatetheorganismfromthe environment
2.SocialBehaviorinEpithelia
Epithelialcellsrespondtotheir environment
Cells interact with their social
environment triggering biological
events:
Ø Proliferation.
Ø Scheduled death.
Ø Movement.
Ø Cell type transitions.
Ø Release of substances.
Figure 1 from: GemCell: A generic platform for
modeling multi-cellular biological systems. Hila
Amir-Kroll, Avital Sadot, Irun R. Cohen, David Harel.
Theoretical Computer Science, 391, 276–290, 2008.
BiologicalRulesdrivingcellbehavior
Death by Overcrowding: when the cell contacts with an
amount of neighbors overcoming a critical number (4-6
cells), it is set as apoptotic.
Contact inhibition: when the cell contacts with an amount of
neighbors overcoming a critical number (4-6 cells), the plate
and/or a different tissue, its cell cycle is arrested.
Death by Isolation: when the cell fail to attach others after a
critical number of cell cycles, it is set as apoptotic.
PhysiologicalandPathologicalvariantsofBRs
Figure 4 from: Computational investigation of epithelial
cell dynamic phenotype in vitro. Sean HJ Kim, Sunwoo
Park, Keith Mostov, Jayanta Debnath and C Anthony Hunt.
Theoretical Biology and Medical Modelling, 6(8), 2009.
Figure 2 from: Essential operating principles for tumor
spheroid growth. Jesse A Engelberg, Glen EP Ropella and C
Anthony Hunt.BMC Systems Biology, 2:110, 2008.
BiochemicalbasisforBRs
Figure from: Deconstructing p53 transcriptional networks in tumor suppression.
Kathryn T. Bieging and Laura D. Attardi. Trends Cell Biology, 2011.
P53 miss function Phenotype
Fail in Scheduled death BRs
Overcrowding (Tumor)
3. Agent-based Modeling:
A robust approach to simulate
complex processes
InteractiveComputationalUnits
Figures 2 and 3 from: Tutorial on agent-based modeling and simulation. CM. Macal and MJ. North. Journal of Simulation,
4,151-162, 2010.
SynchronizingprocesseswithABM
Agent-BasedModeling enablestosynchronizemultiple complexprocesses
P1
P2
P1
P2
P3
P1
P2
P3
P3
Sequential
Threads
ABM
Figure 1 from: Introduction of an agent-based multi-scale modular architecture for dynamic
knowledge representation of acute inflammation. Gary An. Theoretical Biology and Medical
Modelling, 5:11, 2008.
4. Morphogenesis and Homeostasis
in the skin: a particular case study
EpidermalABMModels
Figure 8 from: Development of a Three Dimensional
Multiscale Computational Model of the Human
Epidermis. Salem Adra, Tao Sun, Sheila MacNeil, Mike
Holcombe, Rod Smallwood. Plos One, 5(1), 2010.
Figure 4 from: Modeling epidermal homeostasis as an approach
for clinical bioinformatics. Niels Grabe, Thora Pommerencke,
Dennis Muller, Simone Huber, Karsten Neuber, Hartmut Dickhaus.
2006.
Epidermalstructure
Figure 1 from: Skin barrier responses to moisturizers. Izabela
Buraczewska. Digital comprehensive Summaries of Uppsala
Dissertations from Faculty of Medicine 381, 2008.
Figure 1 from: Molecular Biology of Keratinocyte Differentiation.
Richard Leon Eckert and Ellen Anne Rorke. Environmental Health
Perspectives, Vol. 80, pp. 109-116, 1989.
Barrierfailsleadingtosystemicsymptomatology
Figure 2 from: Epidermal barrier dysfunction and cutaneous
sensitization in atopic diseases. Akiharu Kubo, Keisuke Nagao, and
Masayuki Amagai. The Journal of Clinical Investigation, 122 (2), 2012.
5. Turn-over Imbalance in Epidermis
as putative explanation for the Skin
Aging
Structuralchangesattheagingskin
Figure 3 from: Structural characteristics of the aging skin: a review.
Miranda A. Farange and Kenneth W. Miller. Cutaneous and ocular
Toxicology, 26: 343-357, 2007.
FailuresinBRleadingtoskinaging
Photo-aging as overall aging model.
Figure 1 from: Solar UV radiation reduces the barrier function of
human skin. Biniek, K et al, 2012. PNAS, 109(42): 17111-17116.
ResultsonComputationalmodels
Failures in Loss of contact-related Biological Rules are being investigated as
major cause of skin aging by using computational models:
Ø Premature Contact Inhibition and Death by Overcrowding explain loss of cell mass
and epidermal thinning in elders.
Ø Aberrant cell migration explain dark spots and impairment in wound healing.
Ø Loss of interaction with fibroblast feeders from the dermis reduces cell growth at the
basal lamina, thus limiting the regenerative potential of the epidermis.
6. Replication-independent
injury in Aging
DNA
NUMTS:MitochondrialDNAinsertionsintothegenome
Duringcancer,agingandotherpathologies,mtDNAfragmentsmovetothe
nucleusandtheyareintegratedintothechromosomes(Crottetal,2005.
Mutat.Res.570,63–70)beingputativecauseof:
Ø Breakdown of functional genes or regulatory
elements.
Ø Epigenetic alterations.
Ø Chromosome instability.
Fig. 1 from Caro et al, 2010.
Mitochondrion. 10, 479–486
Searchingforage-relatedNUMTS
DeepExplorationoftheHumanGenometofindnon-germinalmtDNAsequences.
The major question:
Are NUMTS source of Therapeutic
Targets to fight Aging?
CRISPR/Cas9-drivenNUMTSclearance
NUMTS:MitochondrialDNAinsertionsintothegenome
IsitpossibletorevertsenescencemarkersbyeditingNUMTSinvivo?
Age
NUMTS
Clearance
?
TheInnoHealthITteam
Carolina Pavicic, MSc, PhD student.
Cell Automatons theory to model Epithelial Biology.
Martin Garrido, MSc.
Deep exploration of Human Genome searching for age-related
mithocondrial DNA insertions.
Marius A. Botos, MSc.
Mithocondrial DNA insertions with high relevance in aging.
Diana Vega, MSc.
Identification of novel therapeutic targets from complex
biochemical networks.
Eduardo Muñoz, MBA.
He pays our salaries.