PROJECT PROPOSAL - XXXVII cycle - Unimi
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PROJECT PROPOSAL - XXXVII cycle
PROJECT TITLE IN ENGLISH Impact of Drp1 activation, Unfolded Protein Response induction and FGF21
levels in DMD progression
TITOLO DEL PROGETTO Ruolo dell attivazione di Drp1 nella patogenesi della Distrofia Muscolare di
IN ITALIANO Duchenne ed identificazione di FGF21 come marker di severità
TUTOR Clara De Palma
(inclusa la matricola) Mat 46525
E-MAIL clara.depalma@unimi.it
LABORATORY Biometra Department, Via Vanvitelli 32
DEPARTMENT Skeletal muscle and mitochondria biology lab
If available provide a link to
your webpage
DMD shares common mitochondrial alterations with various mitochondrial diseases
and with aged skeletal muscle, including often comparable symptomology. A
plethora of defects in the cellular energy system have been reported in dystrophin-
deficient skeletal muscle in both human patients and animal models, which would
contribute to the failure of energy homeostasis observed in DMD.
Alongside metabolic dysfunctions, mdx fibers reveal dramatic mitochondrial
fragmentation, however, few studies have addressed mitochondrial dynamics.
Mitochondria are dynamic organelles, whose morphology and function are
controlled by a balance between fission and fusion events, and, particularly in
muscle, mitochondria create a network showing mostly tubular morphology.
Giacomotto and colleague reported for the first time that mitochondria
fragmentation occurs in dystrophic nematodes and a zebrafish model for DMD.
They also demonstrate that repression of the mitochondria fission gene drp-1 is
beneficial toward muscle degeneration. Thereafter, the issue has been studied in
mdx/U / ice e eali g ha D 1 e e ion increases more in comparison to
PROJECT
that of mitofusin 2, still suggesting an unbalance of mitochondrial dynamics towards
Provide a general overview of
fission. Recently mitochondrial fragmentation has been associated with IP3 receptor
the rationale and the topic of
(IP3R1) demonstrating that IP3R1 knockdown modulates mitochondrial dynamics
the project and its specific
by decreasing expression of both Drp1 and Fis1 in adult mdx fiber.
goals. Maximum of 750 words.
Emerging evidence suggests that in muscle excessive fission can enhance a general
retrograde response from the mitochondria to the nucleus activating the expression
of nuclear genes as an adaptive response to mitochondrial stress, according to the
concept of mitohormesis. Therefore, mitochondria dynamics act as a signaling hub
triggering a cascade of events that reverberates to the whole body, affecting general
metabolism and aging.
The UPR activation, especially in muscle, induces the expression and release of
FGF21, a mitokine and mediator of mitochondrial stress. FGF21 promotes longevity
and protects against pathologic cardiac hypertrophy, oxidative stress, and
myocardial infarction, however, its high levels in adult-hood contribute to a general
pro-senescence metabolic shift, altered glucose homeostasis, and elevated
inflammatory state with an increase of circulating cytokines. The role of UPR as
well as the data regarding the production of FGF21 in DMD are limited and
considering that its levels depend on the severity of the mitochondrial damage, our
study would succeed to fill the gap, performing an analysis at different stages of
muscle wasting, to address whether and how FGF21 could impact on dystrophic
phenotype and to understand whether FGF21 could be involved in pathogenetic
mechanisms associated to DMD.
We could provide data regarding the use of FGF21 as a marker of severity, thus
confirming the recent idea that DMD shares many similarities with mitochondrial
diseases that, next, it would be worth validating in patients. Besides, the second goal
of the project will lead to identify a hitherto unexploited strategy to fight DMD,
which can result in new exciting studies with other similar molecules that could be
tested in different models of DMD, fulfilling the strong need to develop new,
affordable drugs with minimal side effects to complement, and combine with,
existing therapies.
The final outcome of this project is to investigate the Drp1-dependent induction of
FGF21 and its impact on the disease progression, thus providing a correlation
between DMD hallmarks and FGF21 levels. We will also attempt an innovative
pharmacological strategy, targeting Drp1 to limit the mitohormetic response and the
FGF21 increase.
We will pursue these goals with two different aims:
AIM1 will be focused on exploring the pathways activated by Drp1 leading to
FGF21 expression in DMD. We plan to examine the signaling cascade associated
with altered mitochondrial dynamics, assessing its dependent nuclear response and
defining the molecules involved in increasing FGF21 levels. We will outline the
onset of FGF21 production and its levels at different stages of DMD and we will act
on Drp1 and mitochondrial fission to modulate UPR and FGF21 levels, treating mice
with specific Drp1 inhibitors. Therefore, we could highlight new potential drugs for
alternative mitochondrial targeting therapy
AIM2 will be focused on exploring the systemic/muscular effects associated with
FGF21 levels in dystrophic conditions. FGF21 can mediate unhealthy actions that
will be assessed in mdx mice establishing the relationship between FGF21 levels
and their systemic/muscular effects. Besides, pharmacologically/genetically
blocking the mitokine we will provide the evidence whether blocking FGF21 we
could ameliorate disease progression.
Gli studenti devono essere interessati ad approfondire i meccanismi molecolari
EVENTUALI REQUISITI associati a disfunzioni mitocondriali e responsabili della progressione della distrofia
SPECIFICI DEL CANDIDATO muscolare di Duchenne con la possibilità di eseguire studi preclinici nel modello
murino di DMD.L di dei i c d i c e de a i a e i, dall i agi g alla bi chi ica, e
consente di affrontare diverse tecniche e lo studio in vivo sarà focalizzato sulla
modulazione dei target identificati con approcci multipli, per migliorare il fenotipo
distrofico
Students should be interested in the investigation of molecular mechanisms
associated with mitochondria and responsible for the progression of DMD and in the
CANDIDATE SPECIFIC setting of preclinical studies with the DMD mouse model. The study of mitochondria
REQUIREMENTS (IF ANY) will cover different topics from the imaging to the biochemistry with the possibility
to explore many technics. Besides, this project will give a chance to set up in vivo
approaches to improve the dystrophic phenotype
Giovarelli M, Zecchini S, Martini E, Garrè M, Barozzi S, Ripolone M, Napoli L,
Coazzoli M, Vantaggiato C, Roux-Biejat P, Cervia D, Moscheni C, Perrotta C,
Parazzoli D, Clementi E, De Palma C*. Drp1 overexpression induces desmin
disassembling and drives kinesin-1 activation promoting mitochondrial
trafficking in skeletal muscle. Cell Death and Differentiation. 2020
Filipe A, Chernorudskiy A, Arbogast S, Varone E, Villar-Quiles RN, Pozzer D,
Moulin M, Fumagalli S, Cabet E, Dudhal S, De Simoni MG, Denis R, Vadrot N,
Dill C, Giovarelli M, Szweda L, De Palma C, Pinton P, Giorgi C, Viscomi C,
Clementi E, Missiroli S, Boncompagni S, Zito E, Ferreiro A. Defective
MOST RELEVANT endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-
PUBLICATIONS FOR THE related myopathy. Cell Death Differentiation. 2020
Touvier T, De Palma C, Rigamonti E, Scagliola A, Incerti E, Mazelin L, Thomas
PROJECT
JL, D'Antonio M, Politi L, Schaeffer L, Clementi E, Brunelli S. Muscle-specific
Provide here most relevant
Drp1 overexpression impairs skeletal muscle growth via translational
references for the project attenuation. Cell Death and Disease. 2015 Feb 26;6:e1663. doi:
(max 5) 10.1038/cddis.2014.595
De Palma C, Morisi F, Cheli S, Pambianco S, Cappello V, Vezzoli M, Rovere-
Querini P, Moggio M, Ripolone M, Francolini M, Sandri M, Clementi E.
Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell
Death and Disease. 2012
De Palma C, Falcone S, Pisoni S, Cipolat S, Panzeri C, Pambianco S, Pisconti
A, Allevi R, Bassi MT, Cossu G, Pozzan T, Moncada S, Scorrano L, Brunelli S,
Clementi E. Nitric oxide inhibition of Drp1-mediated mitochondrial fission is
critical for myogenic differentiation. Cell Death and Differentiation. 2010
Giovarelli M, Zecchini S, Martini E, Garrè M, Barozzi S, Ripolone M, Napoli L,
Coazzoli M, Vantaggiato C, Roux-Biejat P, Cervia D, Moscheni C, Perrotta C,
Parazzoli D, Clementi E, De Palma C*. Drp1 overexpression induces desmin
disassembling and drives kinesin-1 activation promoting mitochondrial
trafficking in skeletal muscle. Cell Death and Differentiation. 2020
Zecchini S, Giovarelli M, Perrotta C, Morisi F, Touvier T, Di Renzo I, Moscheni
C, Bassi MT, Cervia D, Sandri M, Clementi E, De Palma C*. Autophagy
controls neonatal myogenesis by regulating the GH-IGF1 system through a
NFE2L2- and DDIT3-mediated mechanism. Autophagy. 2019
MOST RECENT PUBLICATIONS Pedrotti S, Caccia R, Neguembor MV, Garcia-Manteiga JM, Ferri G, De Palma
Provide here your most recent C, Canu T, Giovarelli M, Marra P, Fiocchi A, Molineris I, Raso M, Sanvito F,
publications (max 5) Doglioni C, Esposito A, Clementi E, Gabellini D. The Suv420h histone
methyltransferases regulate PPAR-γ and energy expenditure in response to
environmental stimuli. Science Advances. 2019
Pambianco S, Giovarelli M, Perrotta C, Zecchini S, Cervia D, Di Renzo I,
Moscheni C, Ripolone M, Violano R, Moggio M, Bassi MT, Puri PL, Latella L,
Clementi E, De Palma C*. Reversal of Defective Mitochondrial Biogenesis in
Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and
PGC-1α Acetylation. Cell Reports. 2016
Touvier T, De Palma C, Rigamonti E, Scagliola A, Incerti E, Mazelin L, Thomas
JL, D'Antonio M, Politi L, Schaeffer L, Clementi E, Brunelli S. Muscle-specificDrp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death and Disease. 2015 Feb 26;6:e1663. doi: 10.1038/cddis.2014.595 (*corresponding author)
Nel presentare il progetto, il proponente dichiara che:
a) è presente la disponibilità economica e logistica necessaria per lo sviluppo del
progetto proposto che inizierà a ottobre 2021 ed avrà una durata di tre anni;
b) monitorerà con attenzione il progetto così da valutare se possa produrre una
bblica i e ell a c del ie i in caso contrario il proponente cercherà di
coinvolgere il dottorando in un altro progetto di ricerca o nella stesura di una
review così da garantirgli almeno una pubblicazione prima della discussione della
tesi, cui farà seguito, a meno di giustificate eccezioni, almeno una pubblicazione
in cui il lavoro principale dello studente verrà adeguatamente riconosciuto.
In fede,
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