Full professor

email: lpuri@sbpdiscovery.org
phone: 0652310072

OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 09/30/2024)
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NAME: Puri, Pier Lorenzo
eRA COMMONS USER NAME (credential, e.g., agency login): NIHLPURI
POSITION TITLE: Professor, Sanford Burnham Prebys Medical Discovery Institute
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
(if applicable)
Completion Date

University of Rome La Sapienza Undergraduate 05/1991 Internal Medicine
University of Rome La Sapienza M.D. 06/1991 Internal Medicine
University of Rome La Sapienza Postgraduate 05/1997 Internal Medicine
University of Rome La Sapienza Residency 05/1997 Internal Medicine
University of California, San Diego Postdoctoral 06/2000 Biology

A. Personal Statement.
As an MD, I embraced basic research during my internship in internal medicine, with the ultimate goal of understanding the molecular pathogenesis of untreatable diseases. I have gradually committed my research to the study of neuromuscular disorders, and in particular muscular dystrophies. During my postdoc and the following 15 years of independent PI activity I have focused on investigating the biological, molecular and epigenetic underpinnings of muscle repair in normal conditions or disease, with a special emphasis on muscular dystrophies. My group is especially interested in the mechanism by which different cell types that compose the regenerative niche control the activity of muscle (satellite) stem cells through a network of reciprocal signals, and how these environmental cues are converted into the epigenetic information that regulates gene expression in these cell types. This work is aimed at the elucidation of the molecular pathogenesis of muscular dystrophies, with a special emphasis on the transition from the compensatory regeneration to the pathological fibrotic and fatty degeneration that typically underlies the most dramatic stage during progression of many muscular dystrophies. Indeed, we have discovered that this stage is also the most susceptible to the beneficial effects of potential pharmacological interventions, as it offers a window of opportunity to extend the compensatory regeneration stage, thereby preventing the most deleterious events in the natural history of muscular dystrophies. The ultimate goal of this effort is to identify novel targets for pharmacological interventions toward promoting therapeutic regeneration of diseased muscles. In this regard, work from my lab has identified a deregulated HDAC activity in dystrophic muscles as a key pathogenic event downstream of the dystrophin mutation in Duchenne Muscular Dystrophy (DMD), thereby linking for the first time the genetic mutation with potential epigenetic alterations. This finding has inspired the development of pharmacological interventions with HDAC inhibitors (HDACi) in mouse models of muscular dystrophies that revealed to be effective in promoting regeneration and preventing fibroadipogenic degeneration. Of note, these interventions have been recently translated into a currently ongoing clinical trial with the HDACi Givinostat on DMD boys, in collaboration with Italfarmaco. A current effort of my group is to investigate the molecular and epigenetic determinants by which changes in 3D-genome organization regulate gene expressionby in muscle cells during proliferation and differentiation, using a combination of genome-wide approaches that include 3C-related technologies (i.e. HiC), ATACseq, ChIPseq and RNAseq at bulk and single cell level.

B. Positions, Scientific Appointments, and Honors

Positions and Employment:
2020-present Program Director (Development Aging and Regeneration -DARe – Program)
2015-present Professor, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
2012-2019 Lab Director, Fondazione S. Lucia, Roma, Italy
2012 Senior Telethon Scientist, Dulbecco Telethon Institute, Roma, Italy (position declined)
2010-2012 Associate Professor, Sanford-Burnham Medical Research Institute, La Jolla, CA
2008-2012 Associate Member, Sanford Children’s Health Research Center
2008-2016 Adjunct Professor of Pediatrics, University of California, San Diego, La Jolla, CA
2007-2012 Associate Telethon Scientist, Dulbecco Telethon Institute (DTI), Roma, Italy
2004-2010 Assistant Professor, Sanford-Burnham Medical Research Institute, La Jolla, CA
2002-2006 Assistant Telethon Scientist, Dulbecco Telethon Institute (DTI), Roma, Italy
2001-2004 Staff Scientist, Peptide Biology Laboratory, Salk Institute, La Jolla, CA

Other Experiences and Professional Memberships:
2020-2024 Member of the Science Advisory Board (SAB) European Commission-funded Consortium BIND (Brain Involvement in Dystrophinopathies)
2015-2019 Standing Member, NIH Study Section (SMEP)
2010-present Member of Editorial Board of Skeletal Muscle
2003-2013 Ad Hoc Member of NIH Study Sections (2003, 2007, 2008, 2013, 2019, 2020, 2021)
2002-present Member of Editorial Board of Journal of Cellular Physiology
2001-present Member of Editorial Board of Cancer Biology and Therapy
Feb-Mar 1997 Visiting Scientist at the Freien University of Berlin, Germany
Feb-Mar 1995 Visiting Scientist at the Freien University of Berlin, Germany
Jan-Feb 1994 Visiting Scientist at the Freien University of Berlin, Germany

2002-2004 American Heart Association Beginning Grant-in-Aid
2000-2003 MDA Development Grant
1998-2000 Recipient of a Human Frontier Fellowship
1992-1997 Recipient of a CEE Fellowship for a Postgraduate School of Internal Medicine

C. Contributions to Science

1. Epigenetic regulation of skeletal myogenesis by histone acetyltransferases and deacetylases
In my early studies, I identified and characterized the transcriptional co-activators (the acetyltransferases p300/CBP and PCAF)1 and co-repressors (the histone deacetylases HDACs)2 of the myogenic determination factor MyoD. This work moved forward the field of cellular differentiation beyond the earlier identification of MyoD, by revealing the first epigenetic determinants of skeletal myogenesis, and inspired the experimental rationale toward exploiting pharmacological inhibition of HDAC to promote skeletal myogenesis3,4.
1) Puri P.L., Sartorelli V., Yang X.J., Hamamori Y., Ogrizko , Howard B., Kedes L, Wang J.Y.J., Graessmann A., Nakatani Y., Levrero M. Differential roles of p300 and PCAF acetyltransferases in muscle differentiation. Mol. Cell 1, 35-45 (1997)
2) Puri P.L., Iezzi, S., Stiegler P., Chen T.T., Shiltz L., Muscat G., Giordano A, Wang J.Y.J. and Sartorelli V. Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. Mol Cell. 8, 885-897 (2001)
3) Iezzi S., Cossu G., Nervi C. Sartorelli V., and Puri P.L. Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases Proc. Natl. Acad. Sci 99, 7757-7762 (2002)
4) Iezzi S., Di Padova M., Serra C., Caretti G., Simone C., Maklan E., Zhao P., Hoffman E., Puri P.L. and Sartorelli V. Deacetylase Inhibitors Increase Muscle cell Size by Promoting Myoblast Recruitment and Fusion Through Induction of Follistatin. Dev. Cell. 5:673-84. (2004).
2. HDAC inhibitors as pharmacological intervention in DMD and other muscular dystrophies
My group discovered that dystrophin-activated nNOS signalling controls HDAC2 activity, thereby revealing a previously unrecognized link between constitutive activation of HDAC2 and alteration of the epigenetic landscape of dystrophin-deficient muscles6. This discovery paved the way to establish the rationale for using HDAC inhibitors to enhance muscle regeneration and counter the progression of Duchenne muscular dystrophy (DMD)5-8. Our pre-clinical work on the use of HDACi for the treatment of muscular dystrophies5 has led to their translation into a currently ongoing clinical trial with the HDACi Givinostat in DMD boys. The use of HDACi in DMD is the subject of the following patent issued: Methods of Using Deacetylase Inhibitors to Promote Cell Differentiation and regeneration, NIH/Salk, 2001. US Patent 7229963 - US Patent Issued on June 12, 2007. Estimated Patent Expiration Date: Icon_subject October 17, 2022.
5) Minetti G. C., Colussi c., Adami R., Serra C., Mozzetta C., Parente V., Illi B., Fortuni S., Straino S., Gallinari P., Steinkhuler C., Capogrossi M., Sartorelli V., Bottinelli R., Gaetano C., Puri P.L. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat. Med. 12 (10): 1147-50 (2006)
6) Colussi C., Mozzetta C., Gurtner A. , Illi B., Straino S., Ragone G., Pescatori M., Zaccagnini G., Rosati G., Minetti G., Martelli F., Ricci E., Piaggio G., Gallinari P., Steinkulher C., Capogrossi M.C., Puri P.L*, Carlo Gaetano. A Common Epigenetic Mechanism Underlies Nitric Oxide Donors and Histone Deacetylase Inhibitors Effect in Duchenne Muscular Dystrophy. Proc. Natl. Acad. Sci 105, 19183-7 (2008) *Corresponding authors.
7) Mozzetta C., Consalvi S., Saccone V., Tierney M., Diamantini A., Mitchel K.J., Marazzi G., Borsellino G., Battistini L., Sassoon D., Sacco A., Puri P.L. Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old mdx mice. EMBO Mol. Med. (2013), Mar 18. doi: 10.1002/emmm.201202096. PMCID: PMC3628105
8) Sandonà M, Consalvi S, Tucciarone L, De Bardi M, Scimeca M, Angelini DF, Buffa V, D'Amico A, Bertini ES, Cazzaniga S, Bettica P, Bouché M, Bongiovanni A, Puri PL, Saccone V. HDAC inhibitors tune miRNAs in extracellular vesicles of dystrophic muscle-resident mesenchymal cells. EMBO Rep. 2020 Sep 3;21(9):e50863. doi: 10.15252/embr.202050863. Epub 2020 Aug 5. PMID: 32754983
3. Control of chromatin structure in muscle cells by regeneration-induced signaling pathways
Following up the discovery and characterization of intracellular signaling pathways (i.e. p38, ERK and AKT cascades) that regulate muscle gene expression in myoblasts during my PhD training, studies from my lab have revealed the mechanism by which muscle environmental cues are converted into epigenetic changes that regulate gene expression in healthy and diseased muscles, via extracellular signal-activated kinase targeting of chromatin-modifying enzymes. We have provided the first evidence of a signaling directly linking regeneration cues that activate the p38 pathways with SWI/SNF-mediated chromatin remodeling at myogenic loci of muscle progenitors9. Further studies have discovered how regeneration cues can coordinate gene expression in muscle satellite cells, through signaling pathways that target distinct chromatin-modifying complexes, including acetyltransferases, HDAC, SWI/SNF and Polycomb Repressory Complex (PCR2)9-12.
9) Simone C., Forcales S.V., Hill D., Imbalzano A.L., Latella L., and Puri P.L. p38 Pathway Targets SWI/SNF Chromatin Remodeling Complex to Muscle-Specific Loci. Nat. Genet. 36, 738-43 (2004).
10) Serra C., Palacios D., Mozzetta C Forcales S., Ripani M., Morantte I., Jones D. Du K., Jahla U., Simone C., Puri P.L. Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/Pi3K/AKT pathways during muscle differentiation. Mol Cell. 28, 200-213 (2007). PMCID: PMC2693200
11) Palacios D., Mozzetta C., Consalvi S., Caretti G., Saccone V., Proserpio V., Marquez V.E., Valente S., Mai A., Forcales S., Sartorelli V., Puri P.L. TNF/p38 alpha/Polycomb signalling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 2010 Oct 8;7(4):455-69. PMCID: PMC2951277.
12) Forcales S., Albini S., Giordani L., Malecova B., Cignolo L., Chernov A., Coutinho P., Saccone V., Consalvi S., Williams R., Wang K., Wu Z., Baranovskaya S., Miller A., Dilworth F., Puri P.L. Signal dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodeling complex. EMBO J. 2012 Nov 8;31(2):301-16. PMCID: PMC3261556.
4. Epigenetic basis for activation of the myogenic program in ESCs and other pluripotent cell types
In a parallel effort, we have studied the epigenetic determinants of hESC commitment to skeletal myogenesis, by investigating the hESC resistance to direct conversion into skeletal muscle upon ectopic expression of MyoD, which otherwise reprograms somatic cells into the skeletal muscle lineage. This bottleneck has prevented the generation of “in dish” models of human neuromuscular diseases by hiPSC, at variance with the majority of other cell types. We have discovered that hESC resistance to myogenic conversion is caused by the lack of expression of one structural component of the SWI/SNF chromatin remodelling complex – BAF60C – which is specifically induced in embryoid bodies13. Based on these studies, we have recently established a protocol of hESC-derived 3D contractile myospheres that offers the unprecedented opportunity to dissect and analyze the epigenetic dynamics that underlie the formation of skeletal muscles and to identify changes in the epigenome induced by contractile activity in healthy vs dystrophin-deficient myofibers13. We have also determined the identity of the general transcription factors implicated in the activation of skeletal myogenesis14, and we have discovered that replicative senescence is associated with acquisition of resistance to MYOD-mediated activation of muscle gene expression, caused by the constitutive activation of DNA damage repair (DDR) response that impairs cell cycle progression and MYOD activity15. Finally, our recent work has elucidated the mechanism by which MYOD regulated high-order chromatin interactions to define the tri-dimensional nuclear architecture for the activation of skeletal myogenesis during human somatic cell reprogramming into skeletal muscle.
13) Albini S., Coutinho P., Malecova B., Giordani L., Savchenko A., Forcales S, Puri P.L. Epigenetic reprogramming of human embryonic stem cells (hESCs) into skeletal muscle cells and generation of contractile myospheres. Cell Rep. (2013), Mar 6. pii: S2211-1247(13)00071-5. PMCID: PMC3625045.
14) Malecova B., Dall'Agnese A., Madaro L., Gatto S., Coutinho Toto P., Albini S., Ryan T., Tora L., Puri PL. TBP/TFIID-dependent activation of MyoD target genes in skeletal muscle cells. Elife Feb 25;5. pii: e12534. doi: 10.7554/eLife.12534. PMCID: PMC4775216
15) Latella L., Dall’Agnese A, Boscolo F., Nardoni C. Cosentino M., Lahm A, Sacco A., Puri P.L. DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev. 2017 Apr 1; 31(7):648-659. doi: 10.1101/gad.293266.116. PMCID: PMC5411706
16) Dall’Agnese A., Caputo L., Nicoletti C., di Iulio J., Schmitt A., Gatto S., Diao Y., Ye Z., Forcato M., Perera R., Bicciato S., Telenti A., Ren B., Puri P.L. Transcription Factor-Directed Re-Wiring of Chromatin Architecture for Somatic Cell Nuclear Reprogramming Toward Trans-differentiation. Mol Cell Aug 20. pii: S1097-2765(19)30591-X. doi: 10.1016/j.molcel.2019.07.036. [Epub ahead of print] PMID: 31519520

5. Identification, functional, phenotypic and molecular characterization of muscle-interstitial cells – (the fibroadipogenic progenitors – FAPs) in healthy and diseased muscles.
Our work has elucidated the molecular determinants of the interplay between adult muscle stem cells and cellular components of their functional niche (i.e. FAPs), by identifying regulatory networks implicated in compensatory or pathogenic regeneration, and suggesting “disease stage-specific” responses to pharmacological treatment of neuromuscular disorders, such as DMD. Indeed, we have shown that HDACi promote compensatory regeneration and prevent fibro-adipogenic degeneration in mdx mice at early stages of diseases, by targeting a population of muscle interstitial cells – FAPs7 - and have identified a HDAC-regulated network that controls expression of myomiRs and alternative incorporation of BAF60 variants into SWI/SNF complexes to direct the pro-myogenic or fibro-adipogenic FAP activity17. Furthermore, we have recently identified specific subpopulations of FAPs (subFAPs) in physiological conditions and disease18 and we have discovered that specific subFAPs expand and adopt pathogenic phenotypes upon muscle denervation19 or in muscles of patients affected by diabetes20.
17) Saccone V, Consalvi S, Giordani L, Mozzetta C, Barozzi I, Sandoná M, Ryan T, Rojas-Muñoz A, Madaro L, Fasanaro P, Borsellino G, De Bardi M, Frigè G, Termanini A, Sun X, Rossant J, Bruneau BG, Mercola M, Minucci S, Puri P.L. HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes Dev. 2014 Apr 15; 28(8):841-57. doi: 10.1101/gad.234468.113. Epub 2014 Mar 28. PMCID: PMC4003277
18) Malecova B., Gatto S., Etxaniz U, Passafaro M. Cortez A., Nicoletti C., Giordani L., Torcinaro A., De Bardi M., Bicciato S., De Santa F., Madaro L, Puri PL. Spectrum of cellular states within Fibro-Adipogenic Progenitors upon physiological and pathological perturbations of skeletal muscle. Nat Commun. 2018 Sep 10;9(1):3670. doi: 10.1038/s41467-018-06068-6.
19) Madaro L, Passafaro M., Sala D., Etxaniz U., Lugarini F, Proietti D., Alfonsi MV, Nicoletti C., Gatto S., De Bardi M., Rojas-García R, Giordani L., Marinelli S., Pagliarini V., Sette C, Sacco A, Puri PL. Denervation-activated STAT3-IL6 signaling in fibro-adipogenic progenitors (FAPs) promotes myofibers atrophy and fibrosis. Nat Cell Biol. 2018 Aug; 20(8):917-927. doi: 10.1038/s41556-018-0151-y. PMCID: PMC6145844
20) Consalvi S, Tucciarone L, Macrì E, De Bardi M, Picozza M, Salvatori I, Renzini A, Valente S, Mai A, Moresi V, Puri PL. Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors. EMBO Rep. 2022 Jun 7;23(6):e54721. doi: 10.15252/embr.202254721. Epub 2022 Apr 4. PMID: 35383427

Complete List of Published Work in My Bibliography

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