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Most relevant • n. esteras, c. alquézar, a. de la encarnación, a. VillareJo, F. berMeJo-PareJa, Martín-
requero a. http://www.ncbi.nlm.nih.gov/pubmed/24499616. Calmodulin levels in
scientific
blood cells as a potential biomarker of Alzheimer’s disease. Alzheimers Res Ther.
articles
(2013) 5(6):55.

• n. e, c. a, e. b, F. b-P, u. W, a. M-r-
steraslquézarialoPiotroWiczerMeJoareJaoJdaartíneque
ro. Downregulation oof extracellular signal-regulated kinase 1⁄2 activity by Calmodu-
lin KII modulatesp21(Cip1) levels and survival of immortalized lymphocytes from

Alzheimer’s disease patients. Neurobiol Aging (2013) 34(4):1090-100.

• c. alquezar, n. esteras, ana de la encarnación, a. Martín-requero. Therapeutic Ap-
proaches for the treatment of frontotemporal lobar degeneration. Current Topics in

Pharmacology (2013) Vol 17, 1, 85-101.

• Fernández d, horrillo a, alquezar c, González-Manchón c, Parrilla r, ayuso Ms [2013]

Control of cell adhesion and migration by Podocalyxin. Implication of Rac1 and
Cdc42. Biochem. Biophys. Res. Commun. (2013) 432(2):302-7.

We have completed the development and phenotypic characterization of mouse
Highlights
models with tissue-specific CD40L deletion. Ablation of CD40L at different stages
í
of hematopoietic development has provided important information on the patho-
genesis and clinical manifestations of X-linked-hyper-IgM (ORPHA69712), rare di-

sease due to mutations in the Cd40lg gene. Publication of this work has led to in-

teresting collaborations with foreign groups to study other aspects of the disease.

Studies in a mouse model deficient in podocalicina (Podxl) generated in our labo-
ratory have revealed the role of this protein in the control of vascular permeability

and indicate that these animals represent an excellent tool for studying vasculitis

( ORPHA52759 ), group of rare diseases for which there is so far no animal model
genetically modified, so that the patentability of this model is being evaluated.

We have shown that CDK6/pRb can be considered as a novel theraputic target for

FTLD associated to PGRN deficiency.

Since CDK6 can be epigenetically regulated, we hypothesized that the repositio-
ning of drugs, such sodium butyrate, an inhibitor of histone deacetylases, may
í
provide some hope for treatment of FTLD.
á

By studying the signaling pathways affected by PGRN deficiency, we found altera-

tions in ERK1/2 cascade that seem to be responsible for the increased activation
of CDK6. Thus, the repositioning of Selemetunib and MEK162, two ERK1/2 inhibi- ó

tors already used in cancer treatment, was considered for FTLD. Both drugs were
effective in restoring the normal response to serum stimulation or deprivation of ó

PGRN-deficient cells.
ó
In addition, we had evaluated the effect of restoring PGR levels by drugs able to

increase the protein content at the transcriptional or postranslational level.
13
20
We have found alterations in calmodulin levels in non-neuronal cells and plasma T
of Alzheimer’s disease patients, that could be useful as biomarker for the early OR
P
diagnosis.
RE
L
FUNDING:
A
NU
• SAF2011-28603 (2012-2014) PI: A. Martn Requero
N
A
• XVI Convocatoria. Enfermedades raras. Fundacin Ramn Areces (2012-2015) R /
E
PI: A. Martn Requero
ER
B
• BFU2010-15237 (2011-2014) PI: C. Gonzlez Manchn
CI

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