PEOPLE

Alessandra Chesi, PhD

Assistant Professor of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania

Contact InformationDepartment of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania
Room 605A, Stellar Chance Laboratories
422 Curie Blvd.
Philadelphia, PA, 19104

Specialty Division

Immunobiology and Experimental Pathology

Research Expertise

Research Interests:
Our lab's goal is to translate genetics findings from GWAS and sequencing studies of human neurodegenerative disorders into molecular mechanisms of disease, with the aim of identifying actionable target genes.

Keywords:
neurogenetics, bioinformatics, 3D genomics, Alzheimer's disease, Parkinson's disease, neurodegeneration, iPSC-derived neural cells

Techniques:
Capture C, ATAC-seq, ChIP-seq, RNA-seq, CRISPR/Cas9

Research summary:
Genetic studies have provided a wealth of variants associated with human complex traits, but are not able to pinpoint the underlying target genes and molecular mechanisms. We are interested in finding the target genes for several brain-related disorders, such as Alzheimer's, Parkinson's and other neurodegenerative disease. To do this, we use a combined wet-bench/bioinformatic approach, leveraging cutting-edge genomics and epigenetic techniques such as Capture C, ATAC-seq, ChIP-seq, and RNA-seq plus custom analysis pipelines and methods to perform a “variant-to-gene mapping” campaign for these disorders. We follow up candidate culprit variant-gene pairs by CRISPR/Cas9 editing and functional studies in appropriate cellular models of neurodegeneration, such as iPSC-derived neurons (cortical, dopaminergic, etc.), microglia, astrocytes, co-cultures and cerebral organoids (“brain in a dish”). Our ultimate goal is drug discovery for the identified target genes/molecular pathways, utilizing our cellular models of neurodegeneration for drug screens and leveraging system biology approaches.

Rotation projects:
Please contact Dr. Chesi to discuss possible rotation projects.

Graduate Groups

Cell and Molecular Biology

Education

M.Sc. (Physics), University of Pisa, Italy, 2002
PhD (Structural and Functional Genomics), International School for Advanced Studies (SISSA/ISAS), Trieste, Italy, 2007

Specialty Certification

Postgraduate Training

Postdoctoral fellow, Cell & Dev Biology, University of Pennsylvania, 2008-2011
Postdoctoral fellow, Genetics, Stanford University, 2012-2012

Awards and Honors

M.Sc. in Physics awarded with high honors (Cum Laude), University of Pisa, 2003
CBM/WARTSILA prize for outstanding doctoral dissertation in Genomics, 2007
Parkinson’s Disease Foundation Postdoctoral Fellowship, 2008-2010
2nd prize in the Center for Neurodegenerative Disease Research Retreat Poster Contest, 2008
ASN (Italian National Scientific Qualification in Genetics at the Associate Professor level), 2017-2026

Memberships and Professional Organizations

American Society for Human Genetics, 2015 - Present
American Society for Bone Mineral Research, 2015 - Present

Web Links


Selected Publications

Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.

Su C, Johnson ME, Torres A, Thomas RM, Manduchi E, Sharma P, Mehra P, Le Coz C, Leonard ME, Lu S, Hodge KM, Chesi A, Pippin J, Romberg N, Grant SFA, Wells AD, Nature communications 11(1): 3294, 2020, PMID:32620744

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Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver.

Çalışkan Minal, Manduchi Elisabetta, Rao H Shanker, Segert Julian A, Beltrame Marcia Holsbach, Trizzino Marco, Park YoSon, Baker Samuel W, Chesi Alessandra, Johnson Matthew E, Hodge Kenyaita M, Leonard Michelle E, Loza Baoli, Xin Dong, Berrido Andrea M, Hand Nicholas J, Bauer Robert C, Wells Andrew D, Olthoff Kim M, Shaked Abraham, Rader Daniel J, Grant Struan F A, Brown Christopher D, American journal of human genetics 105(1): 89-107, 2019, PMID:31204013

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Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density.

Chesi Alessandra, Wagley Yadav, Johnson Matthew E, Manduchi Elisabetta, Su Chun, Lu Sumei, Leonard Michelle E, Hodge Kenyaita M, Pippin James A, Hankenson Kurt D, Wells Andrew D, Grant Struan F A, Nature communications 10(1): 1260, 2019, PMID:30890710

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A Genomewide Association Study Identifies Two Sex-Specific Loci, at SPTB and IZUMO3, Influencing Pediatric Bone Mineral Density at Multiple Skeletal Sites.

Chesi Alessandra, Mitchell Jonathan A, Kalkwarf Heidi J, Bradfield Jonathan P, Lappe Joan M, Cousminer Diana L, Roy Sani M, McCormack Shana E, Gilsanz Vicente, Oberfield Sharon E, Hakonarson Hakon, Shepherd John A, Kelly Andrea, Zemel Babette S, Grant Struan Fa, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32(6): 1274-1281, 2017, PMID:28181694

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BMD Loci Contribute to Ethnic and Developmental Differences in Skeletal Fragility across Populations: Assessment of Evolutionary Selection Pressures.

Medina-Gómez Carolina, Chesi Alessandra, Heppe Denise H M, Zemel Babette S, Yin Jia-Lian, Kalkwarf Heidi J, Hofman Albert, Lappe Joan M, Kelly Andrea, Kayser Manfred, Oberfield Sharon E, Gilsanz Vicente, Uitterlinden André G, Shepherd John A, Jaddoe Vincent W V, Grant Struan F A, Lao Oscar, Rivadeneira Fernando, Molecular biology and evolution 32(11): 2961-72, 2015, PMID:26226985

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A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius.

Chesi Alessandra, Mitchell Jonathan A, Kalkwarf Heidi J, Bradfield Jonathan P, Lappe Joan M, McCormack Shana E, Gilsanz Vicente, Oberfield Sharon E, Hakonarson Hakon, Shepherd John A, Kelly Andrea, Zemel Babette S, Grant Struan F A, Human molecular genetics 24(17): 5053-9, 2015, PMID:26041818

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Cirulli Elizabeth T, Lasseigne Brittany N, Petrovski Slavé, Sapp Peter C, Dion Patrick A, Leblond Claire S, Couthouis Julien, Lu Yi-Fan, Wang Quanli, Krueger Brian J, Ren Zhong, Keebler Jonathan, Han Yujun, Levy Shawn E, Boone Braden E, Wimbish Jack R, Waite Lindsay L, Jones Angela L, Carulli John P, Day-Williams Aaron G, Staropoli John F, Xin Winnie W, Chesi Alessandra, Raphael Alya R, McKenna-Yasek Diane, Cady Janet, Vianney de Jong J M B, Kenna Kevin P, Smith Bradley N, Topp Simon, Miller Jack, Gkazi Athina, Al-Chalabi Ammar, van den Berg Leonard H, Veldink Jan, Silani Vincenzo, Ticozzi Nicola, Shaw Christopher E, Baloh Robert H, Appel Stanley, Simpson Ericka, Lagier-Tourenne Clotilde, Pulst Stefan M, Gibson Summer, Trojanowski John Q, Elman Lauren, McCluskey Leo, Grossman Murray, Shneider Neil A, Chung Wendy K, Ravits John M, Glass Jonathan D, Sims Katherine B, Van Deerlin Vivianna M, Maniatis Tom, Hayes Sebastian D, Ordureau Alban, Swarup Sharan, Landers John, Baas Frank, Allen Andrew S, Bedlack Richard S, Harper J Wade, Gitler Aaron D, Rouleau Guy A, Brown Robert, Harms Matthew B, Cooper Gregory M, Harris Tim, Myers Richard M, Goldstein David B, Science 347(6229): 1436-41, 2015, PMID:25700176

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Exome sequencing to identify de novo mutations in sporadic ALS trios.

Chesi Alessandra, Staahl Brett T, Jovičić Ana, Couthouis Julien, Fasolino Maria, Raphael Alya R, Yamazaki Tomohiro, Elias Laura, Polak Meraida, Kelly Crystal, Williams Kelly L, Fifita Jennifer A, Maragakis Nicholas J, Nicholson Garth A, King Oliver D, Reed Robin, Crabtree Gerald R, Blair Ian P, Glass Jonathan D, Gitler Aaron D, Nature neuroscience 16(7): 851-5, 2013, PMID:23708140

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The role of the Parkinson's disease gene PARK9 in essential cellular pathways and the manganese homeostasis network in yeast.

Chesi Alessandra, Kilaru Austin, Fang Xiaodong, Cooper Antony A, Gitler Aaron D, PloS one 7(3): e34178, 2012, PMID:22457822

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Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.

Gitler Aaron D*, Chesi Alessandra*, Geddie Melissa L*, Strathearn Katherine E, Hamamichi Shusei, Hill Kathryn J, Caldwell Kim A, Caldwell Guy A, Cooper Antony A, Rochet Jean-Christophe, Lindquist Susan, Nature genetics 41(3): 308-15, 2009, PMID:19182805

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