outline for MINECO grant with details 02-10-2014d1029



-proteins associated with telomerase and telomeres
{
--TRF1
{
---The Blasco lab has created TRF1 knockout mice, and has demonstrated that TRF1 is critical for the stability of telomeres.  Without TRF1 there are more chromosomal fusions [TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis], increases in cancer [Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice], and bone marrow failure similar to the failure present in the aging syndrome Dyskeratosis congenita [Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of Dyskeratosis congenita].
{
---[TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis]
----TRF1 acts
as a negative regulator of telomere length by controlling XPF activity at telomeres
----K5TRF1 cells also show increased end--to--
end chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact
of TRF1 on telomere integrity
----TRF1 has a unique role in the mitotic
spindle checkpoint
---[Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice]
---[Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of Dyskeratosis congenita]
----Together, these results
represent proof of principle that muta--
tions in TRF1 lead to the main clinical
features of BMF
}
TRF1 is such an important protein that two of the students (María García-Beccaria and Ianire Garrobo) will complete their dissertations with a focus on TRF1 in 2014.
{
---María García-Beccaria will complete her dissertation "Study of TRF1 as a potential therapeutic target for K-rasG12V- induced lung cancer" in 2014
---Ianire Garrobo will complete his dissertation "Identification of new functions of telomeric protein TRF1" in 2014
}
}
--TRF2
{
---Studies of TRF2 revealed that this protein also binds to telomeres and is critical for maintaining telomere stability [Genetic dissection of the mechanisms underlying telomere-associated diseases Impact of the TRF2 telomeric protein on mouse epidermal stem cells] [Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations]
{
---[Genetic dissection of the mechanisms underlying telomere-associated diseases Impact of the TRF2 telomeric protein on mouse epidermal stem cells]
----Altogether, these results indicate that
persisting ESC defects in  K5Tert/K5TRF2  mice are the consequence
of  a  failure  to  rescue  critically  short  telomeres  by  telomerase
overexpression in these mice.
----TRF2 is a central component of the shelterin complex that binds
to  telomeres,  and  has  essential  roles  in  the  protection  of
chromosome  ends  and  regulation  of  telomere  length
---[Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations]
----sing telomerase--de?cient TRF2--overexpressing mice
(K5TRF2/Terc

/

) as a model for accelerated aging, we show that
telomere shortening is paralleled by a gradual deregulation of the
mammalian transcriptome leading to cumulative changes in a de?ned
set of genes, including up--regulation of the mTOR and Akt survival
pathways and down--regulation of cell cycle and DNA repair path--
ways.
----these ?ndings suggest that critically
short telomeres activate a persistent DNA damage response that
alters gene expression programs in a nonstochastic manner toward
cell cycle arrest and activation of survival pathways, as well as impacts
the maintenance of epigenetic memory and nuclear organization,
thereby contributing to organismal aging.
}
}
--TIN2
--POT1
{
---A study of POT1, revealed that POT1 mutations occurred in 3.5% of the chronic lymphocytic leukemia patients investigated [POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia].
{
---[POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia]
----q
	identifying	
recurrent	somatic	mutations	in	POT1	(encoding	protection		
of	telomeres	1)	in	3.5%	of	the	cases,	with	the	frequency	
reaching	9%	when	only	individuals	without	IGHV@	mutations		
were	considered.
}


}
--TPP1
{
---TPP1 recruits the TERT telomerase protein, and is necessary for normal skin development in mice.  Somewhat surprisingly, TPP1 deficient mice that were also deficient in p53 were rescued from the skin hyperpigmentation associated with TPP1 deficiency alone [TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice].  This result highlights the role of p53 in preventing cell division in the presence of telomere damage.
{
---[TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice]
----Here we ?nd that Tpp1--de?cient mouse
embryonic ?broblasts (MEFs) show increased chro--
mosomal instability including sister chromatid
fusions and chromosomes with multitelomeric sig--
nals related to telomere fragility.
----p53 De?ciency Rescues Skin Hyperpigmentation
----upporting a key role of p53 in mediating
proliferative arrest in response to persistent telomere damage
in vivo
and Hair Growth Defects in Tpp1
}

---One student in the lab (Aksinya Derevyanko) will complete his dissertation on TRF1/TRF2/TPP1 gene therapy in 2016.
---Aksinya Derevyanko will complete his dissertation "TRF1/TRF2/TPP1 –AAV9 gene therapy in adult and old WT mice. Impact on lifespan and health parameters" in 2016
}
--RAP1
{
---RAP1 binds to telomere DNA sequences as well as other TTAGGG sites throughout the genome [Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites].  RAP1 knockout mice become obese more quickly than wild type mice, and this is explained by the role of RAP1 as a transcriptional regulator of metabolic pathways [RAP1 protects from obesity through its extratelomeric role regulating gene expression].
{
---[Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites]
----Here we show that Rap1 deficiency is dispensable for telomere capping but leads to increased telomere 
recombination and fragility.
----Rap1 binds to both telomeres and to extratelomeric sites through the (TTAGGG)
2 consensus motif
---[RAP1 protects from obesity through its extratelomeric role regulating gene expression]
----CNIO and NIH paper
----These mice show early onset of obesity,
which is more severe in females than in males
----RAP1 Regulates Ppara and Pgc1a Transcription
----In conclusion, we demonstrate here that RAP1 serves as a
transcriptional regulator that controls the capacity of down--
stream metabolic pathways critical for metabolic maturation
}
}

p53
{
A recent finding indicate that uncapped telomeres prevent cell division through p53 and p21 dependent mechanism [p53 Prevents entry into mitosis with uncapped telomeres].  The p53 protein is also a central modulator of adult neurogenesis [Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis].  The Blasco lab has also explored the relationship between a shelterin protiin and a DNA damage protein and demonstrated that p53BP1 and TRF1 deficiency activates a DNA damage response dependent on the ATR protein [53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response].
--[p53 Prevents entry into mitosis with uncapped telomeres]
---Uncapped Telomeres Trigger ATM- and
p53/p21-Dependent G2/M Arrest
--[Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis]
---Our results suggest that age-related deficits could be caused
partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production
and differentiation of postnatally generated olfactory neurons.
--[53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response]
---53BP1 deficiency significantly 
rescued  telomere  fusions  in  mouse  embryonic  fibro -
blasts  (MEFs)  lacking  TRF1,  but  they  showed  evidence 
of  a  switch  from  the  NHEJ-  to  HR-mediated  repair  
of uncapped telomeres.
---Our work provides the first evidence of deleterious genetic 
interaction between a shelterin component and a DNA damage 
repair component, TRF1 and 53BP1, respectively.
} 


--Maria Blasco has also been involved with many other proteins such as MSH2 and its tumor suppressor activity of short telomeres [MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres], SIRT1 which attenuates telomere shortening with age and even specifically binds to telomeric repeats in iPS cells [SIRT1 contributes to telomere maintenance and augments global homologous recombination], ATR which suppresses telomere fragility but is not necessary for telomerase recruitment to telomeres [ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase], BRCA2 which facilitates telomere replication and capping [BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping], Cohesin-SA1 which prevents aberrant telomeres [Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres], SLX4 which regulates telomeres [Localization-dependent and -independent roles of SLX4 in regulating telomeres], and XPC which prevents telomerase fragility and is involved in the nucleotide excision repair (NER) pathway [Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum].
{
MSH2
{
--[MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres]
---MSH2
deficiency abolishes the tumor suppressor activity of short
telomeres.  Interestingly,  MSH2  deficiency  prevented
degenerative pathologies in the gastrointestinal tract
of 
 
MSH2
 
–/–
 
Terc
 
–/–
 
 mice concomitant with a rescue of pro-
liferative defects.
---MSH2 abrogation rescues aging pathologies 
associated to short telomeres
^this seems surprising to me
----MSH2 abrogation largely abolishes the tumor 
suppressor activity of short telomeres
^so there were more tumors
}


SIRT1
{
--[SIRT1 contributes to telomere maintenance and augments global homologous recombination]
---We studied both loss of function (SIRT1 
deficient) and gain of function (SIRT1 super ) mouse models
---SIRT1 is a positive regulator of 
telomere length in vivo and attenuates telomere shortening associated with aging
---SIRT1 specifically binds to telomeric 
repeats in vivo in induced pluripotent stem 
(iPS) cells
}

ATR
{
--[ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase]
---Generation of mice and cells doubly 
deficient in 
ATR
 and 
Terc
----In conclusion, we show in this study that severe reduction in 
ATR levels does not impair telomerase recruitment to short telo-
meres but increases telomere fragility and telomere recombina-
tion, indicating that the important DDR checkpoint kinases ATM 
and ATR function differently in telomere maintenance in mam-
mals and yeast.
}

BRCA2
{
--[BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping]
---Conditional deletion of Brca2 and inhibition 
of Rad51 in mouse embryonic fibroblasts (MEFs), but not inactivation of Brca1, led to shortening of telomeres and accumulation 
of fragmented telomeric signals
---Telomere homeostasis requires BRCA2
}


Cohesin-SA1
{
--[Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres]
---We propose
a novel mechanism for aneuploidy generation that involves
impaired telomere replication upon loss of cohesin-SA1,
with clear implications in tumourigenesis.
---Aberrant telomeres in cells lacking SA1
}

SLX4
{
--[Localization-dependent and -independent roles of SLX4 in regulating telomeres]
}

XPC
{
--[Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum]
---CNIO paper
---Gerdine Stout and Maria Blasco paper
---corresponding author is Gerdine Stout
---
Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase
suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double
mutants.
----surprising result
---In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated
with an increased tumor incidence, by activating the ALT pathway of telomere lengthening.
---Xpc prevents telomere fragility
---Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-/--mutant mice and Xpc-/-G1-G3Terc-/- double-mutant mice and exposed them to UV radiation.
--XP <- defects in the nucleotide excision repair (NER) pathway
}

}
}

-Telomeric Chromatin
{
--methylations
--TERRA or non-coding telomere RNA
---[TERRA transcripts are bound by a complex array of RNA--binding proteins]
---- In this study, we identify a set of RNA--binding proteins, which endogenously bind and
regulate TERRA in the context of primary mouse embryonic fibroblasts
----TERRA tran-
scripts are bound by a complex set of proteins, being hnRNP A1,
A2B1, F and M the most abundant ones.
--Telomere RNA (TERRA) patent P40524US with Stefan Schöftner and Maria Blasco
}

-Stem cells
{
--Blasco's lab demonstrated that telomeres have embryonic stem cell characteristics in iPS cells, and the length of the telomeres is much longer than in the original cell [Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells].
{
--*[Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells]
}
The p53 protein prevents reprogramming cells to iPS cells in the presence of short telomeres or DNA damage  [A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity].  Abrogation of p53 results in more efficient reprogramming, but the cells could have a higher prevalence of DNA damage and chromosomal aberrations.
{
--[A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity]
---q
Reprogramming in the
presence of pre-existing, but tolerated, DNA damage is aborted
by the activation of a DNA damage response and p53-dependent
apoptosis.
---q
Abrogation of p53 allows efficient reprogramming in
the face of DNA damage and the generation of iPS cells carrying
persistent DNA damage and chromosomal aberrations.
---p53 downregulation improves
reprogramming efficiency 20 .
}
--Inhibiting the Ink4/Arf locus also leads to increased reprogramming efficiency, and this locus can be inhibited with short hairpin RNA [The Ink4/Arf locus is a barrier for iPS cell reprogramming].
{
--[The Ink4/Arf locus is a barrier for iPS cell reprogramming]
--- q
Genetic inhibition of the Ink4/Arf locus has a
profound positive effect on the efficiency of iPS cell generation,
increasing both the kinetics of reprogramming and the number of
emerging iPS cell colonies
----q
this
defect can be rescued by inhibiting the locus with a short hairpin
RNA.
}
--Suv4-20h abrogation results in longer telomeres during reprogramming, but also leads to more cell tumor behavior [Suv4-20h Abrogation Enhances Telomere Elongation during Reprogramming and Confers a Higher Tumorigenic Potential to iPS Cells].
{
--[Suv4-20h Abrogation Enhances Telomere Elongation during Reprogramming and Confers a Higher Tumorigenic Potential to iPS Cells]
}
Additionally, TRF1 has been identified as a stem cell marker that is also necessary to make iPS cells [TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells].
{
--[TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells]
}
--One study revealed that stem cell functionality is inhibited in mice with short telomeres due to the action of p53 [A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres].  Interestingly, p53 abrogation resulted in more epidermal proliferation and some positive effects.
{
--[A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres] 
---Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor
cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on
tissue fitness.
---generating doubly deficient mice for telomerase and p53, Terc
-/
-
p53
-/-
---p53 abrogation could
conceivably restitute stem cells functionality in other organs
}
--Short telomeres also inhibit proliferation and differentiation in neural stem cells [Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis].
{
--[Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis]
---Our results suggest that age-related deficits could be caused
partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production
and differentiation of postnatally generated olfactory neurons.
}
--In another study, the researchers were the first to isolate and characterize colon stem cells [Isolation and in vitro expansion of human colonic stem cells].
{
--[Isolation and in vitro expansion of human colonic stem cells]
---the first 
isolation, characterization and in vitro expansion of a cell popula-
tion largely enriched in human CoSCs.
---CoSc: colon stem cells 
}
--Blasco also helped discover that stem cell exhaustion caused by loss of Cdk7 leads to premature aging [Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion].
{
--[Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion]
---Loss of Cdk7 expression in actively dividing tissues
results in accelerated aging
}


--In a study fundamental to the way stem cell research is performed, Blasco's lab found that the hyper-long telomeres found in embryonic stem cells are an artifact caused by the in vitro establishment and expansion of these cells [Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells].
{
--[Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells]
--q
hyper-long telomeres in ES cell are aberrant and may
result from the in vitro establishment and expansion of ES cells.
}

--Another study explored the fundamental aspects of stem cell division, and the result indicated that stem cells undergo asymmetric division in a manner that segregates the template DNA strands to the stem cell [A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division].
{
--[A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division]
---France Spain Switzerland paper
---Pax7-nGFPHi cells generate distinct daughter cell fates by asymmetrically segregating template DNA strands to the stem cell. These findings provide major insights into the biology of stem cells that segregate DNA asymmetrically

}

--One of the students in the Blasco lab (Miguel Foronda) will complete his dissertation in 2014 on the role of one of these factors (SOX4) in cancer, aging, and tissue homeostasis.
--Miguel Foronda will complete his dissertation "Estudio del papel del factor de transcripción Sox4 en cáncer, envejecimiento y homeostasis tisular" or "Study of the role of transcription factor SOX4 in cancer, aging and tissue homeostasis" in 2014
}


-mouse telomerase models
--*[The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence]
--**[Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer]
---Treatment of 1- and 2-year old mice with an adeno associated virus
(AAV) of wide tropism expressing mouse TERT had remarkable bene?cial effects
---Importantly, telomer-
ase-treated mice did not develop more cancer than their control littermates,
suggesting that the known tumorigenic activity of telomerase is severely
decreased when expressed in adult or old organisms using AAV vectors.
on health and ?tness, including insulin sensitivity, osteoporosis, neuromuscular
coordination and several molecular biomarkers of aging.
---telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in
median lifespan of 24 and 13%, respectively.
--Antonia Tomás-Loba completed her dissertation "Tert y envejecimiento: generación de ratones longevos" or "Tert and aging: the generation of long-lived mice" in 2009
--Juan Manuel Povedano will complete his dissertation "Generation of a mouse model for idiophatic pulmonary fibrosis and study of the molecular mechanism underlying this disease" in 2016
--Patent "Telomerase reverse transcriptase for protection against aging-associated degenerative and inflammatory processes" (EP08169079) for European Union


-calorie restriction and metabolism studies
--In another mouse model, Blasco's lab demonstrated that transgenic TERT mice lived even longer when treated with calorie restriction [Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity].  The calorie restriction also reduced the incidence of neoplasias.
{
--*[Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity]
---Bernardes de Jesus and Maria Blasco
---Spain paper
---q
CR significantly decreased tumor incidence in TERT transgenic (TgTERT) mice and extended their lifespan
---In
particular, although TERT overexpressing mice presented a
higher incidence of neoplasias than WT mice, the incidence of
these neoplasias was reduced to a similar incidence than that of
WT mice under CR
compared to wild-type (WT) controls under the same diet, indicating a synergy between TgTERT and CR in increasing mouse
longevity
}
--[Personal omics profiling reveals dynamic molecular and medical phenotypes]
---Stanford Yale CNIO
---this is pretty neat paper and a glimpse into the future.  It looks at all types of omic data for one individual over 14 months
--*[A metabolic signature predicts biological age in mice]
---q
 de?ne a robust metabolomic signature and a
derived metabolomic score that reliably/accurately predicts the
age of wild-type mice
---TERT-based gene therapy
recently described by us signi?cantly reverted the metabolic
---The age biomarkers identi?ed here include lipids and other small
molecules such as creatine, methionine, and uric acid. Whether these
biomarkers play a role in aging or are due to secondary phenomena will
require further investigation
pro?le of old mice to that of younger mice
---multivariate model with SIMCA - P+ software


-Correlating telomere measurements with health
--HT-QFISH and telomapping
--The amount of short telomeres is positively correlated with the number of depressive episodes of pateints with bipolar disorder [The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder].
{
--[The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder]
---The load of short telomeres was significantly increased in patients with BD-II relative to
healthy controls and may represent 13 years of accelerated aging
---Depressive episode-related stress may accelerate telomere shortening and aging.
}
--The rate of increase of short telomeres predicts longevity in mice, whereas average telomere length does not provide a good predictor [The Rate of Increase of Short Telomeres Predicts Longevity in Mammals].
{
--[The Rate of Increase of Short Telomeres Predicts Longevity in Mammals]
---We
found that mouse telomeres shorten apprx 100 times
---The Rate of Increase in the Per-
centage of Short Telomeres and the Rate
of Telomere Shortening Predicts Mouse
Longevity
}
--Short telomere length is associated with increased ovarian cancer risk [Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases] and breast cancer risk [Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade].
{
--[Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases]
--[Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade]
---B Martinez-Delgado is corresponding author
---We found that hereditary breast
tumor samples showed shorter TL compared to sporadic
---q
In conclusion, telomere dysfunction is frequently
found in hereditary tumors and may be a marker of tumor
aggressiveness in breast cancer patients
breast cancer samples.
}
--Elsa Vera completed her dissertation "Aplicación del método de medida de la longitud telomérica a gran escala HT Q-FISH a estudios de poblaciones humanas, cáncer y envejecimiento." or "Application of the method of measurement of telomere length scale HT Q-FISH studies of human populations, cancer and aging" in 2010  
--Patent "Methods and reagents for the determination of telomere lenght in a semi-automatic manner of every single cell in an immobilized cell population" P3774US00 by Ignacio Flores, Andrés Canela, Elsa Vera and Maria A. Blasco


Other studies
--The research of Maria Blasco is quite diverse.  In one collaboration, she investigates CONSYN-CTCF genomic sites and finds that they precede transcription factors involved in developmental processes [Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes].
{
--Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes
--- CONSYN-CTCF sites preferentially flank transcription factors involved in developmental processes
---increased risk of multiple sclerosis 
located inoutloo the GFI1–EVI5 genomic region
}
--In another collaboration, she investigates pathways involved in the childhood tumors known as adamantinomatous craniopharyngioma [Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma].
{
--[Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma]
--- As
well as providing further support to the concept that pitu-
itary stem cells may play an important role in the
oncogenesis of human ACP, our data reveal novel disease
biomarkers and potential pharmacological targets for the
treatment of these devastating childhood tumours
---London Spain North Carolina paper
}
--In another study she investigates the role of p53 isoforms in T lymphocytes [p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes]
{
--[p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes]
---NIH CNIO, Czech republic, Singapore
---Journal of clinical investigation
---corresponding author is Curtis Harris at NIH
---Knockdown of ?133p53 or overexpression of p53ß induces cellular senes-
cence in CD8 + CD28 +  T lymphocytes.
}


-merits of investigator
{
--reviews, cooperation, awards of mentor, book chapters
--In addition to contributing many research articles to the scientific literature, Maria Blasco has also been an author of many reviews and editorials.  She has written a review on telomeric RNAs [A 'higher order' of telomere regulation: Telomere heterochromatin and telomeric RNAs][Chromatin regulation and non-coding RNAs at mammalian telomeres], high impact papers about aging in 2009 [Impact papers on aging in 2009], the role of telomeres in stem cells [The role of telomeres and telomerase in stem cell aging], the role of shelterin in cancer and aging [Role of shelterin in cancer and aging] [Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins] , telomere rejuvenation when reprogramming cells to iPS cells [Telomere rejuvenation during nuclear reprogramming], genomic instability in iPS cells [Genomic instability in iPS: time for a break], telomeres and aging [Telomeres in cancer and ageing paper][Aging by telomere loss can be reversed][Potential of telomerase activation in extending health span and longevity][Interview: Fighting disease from the chromosome end][Telomerase at the intersection of cancer and aging], measuring telomeres [Beyond average c potential for measurement of short telomeres], and assessing senescence biomarkers [Assessing cell and organ senescence biomarkers].  She was also a co-author on the 2013 paper titled "The Hallmarks of Aging" [The hallmarks of aging] which organized the various topics of aging in a similar manner to the popular papers titled "The Hallmarks of Cancer" in 2000 [The hallmarks of cancer] and 2011 [Hallmarks of cancer: the next generation.].
{
--[A 'higher order' of telomere regulation: Telomere heterochromatin and telomeric RNAs]
--[Chromatin regulation and non-coding RNAs at mammalian telomeres] (review paper)]
---telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of telomere length and telomere chromatin
---review paper
--[Impact papers on aging in 2009] (review paper)
---kind of like a review paper
---discusses Harvard paper
--[The role of telomeres and telomerase in stem cell aging] (review paper)
--[Role of shelterin in cancer and aging]
---review
---some
cases of premature aging in human syndromes have been linked
to shelterin mutations
---the length of telomeres mat-
ters as long as some of the shelterin components are bound to
them
--[Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins] (review paper)
--[2009 nobel prize in physiology or medicine: telomeres and telomerase]
---guest editorial
--[Telomere rejuvenation during nuclear reprogramming] (review paper)
--[Genomic instability in iPS: time for a break] (review paper)
--[Telomeres in cancer and ageing paper] review paper
--[Aging by telomere loss can be reversed]
--[Potential of telomerase activation in extending health span and longevity] (opinion paper)
--[Interview: Fighting disease from the chromosome end]
--[Telomerase at the intersection of cancer and aging] (review paper)
---Bernardes de Jesus and Maria Blasco paper
---CNIO paper
--[Beyond average c potential for measurement of short telomeres] (kind of like a review paper)
--[Assessing cell and organ senescence biomarkers] (review paper)
}
--*[The hallmarks of aging] (review paper)
---CNIO, Max Planck Institute Germany, London, France paper
---corresponding author: Manuel Serrano
---These hallmarks are: genomic instability, telomere attrition, epigenetic alter-
ations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular
senescence, stem cell exhaustion, and altered intercellular communication
--has received funding from 20 different contracts with organizations from around Europe over the last 5 years
--more than 10 awards since 2009
--cooperative with many other institutions and has received the "Spanish Ministry of Foreign Affairs and International Cooperation" or "Embajadora Honoraria de la Marca España" Award
-joined 11 different scientific and advisory boards since 2009
-in 2008 she was also the founding editor of Aging
-she is currently the direcot of CNIO (from 2011)
}


-outlook for future
--capacity of the facility. . Core Units at CNIO provide state-of-the-art facilities and technical expertise to CNIO scientitists
---animal facility, transgenic mice unit, confocal microscopy unit, molecular imaging unit, proteomics unit, and genomics unit