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About

About

Gianluca Ursini, M.D., Ph.D., is an Investigator in Functional Genomics at the Lieber Institute for Brain Development and Assistant Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins School of Medicine. His primary interest is the dynamic interaction between genes and epigenetic factors during brain development and activity. His lab is currently investigating the role of early life (i.e., pre and peri-natal) environment in the pathophysiology of neurodevelopmental disorders. In this regard, Luca has discovered how genomic risk for schizophrenia and severe early life complications impact the risk for the disease through processes involving placental function. Luca attended the University of Bari “A. Moro,” where he received an M.D. in 2002, a residency in Psychiatry in 2006 and a Ph.D. in “Experimental Neurobiology” in 2011. He was drawn into scientific research during his residency training in Psychiatry. Reviewing the medical history of his patients, he was intrigued by the possibility of studying how their diseases developed, which he assumed followed very diverse trajectories. Over the course of his residency and his Ph.D., Luca has been performing studies on schizophrenia using a combination of imaging and genetics techniques, triggering the investigation of the relationship between epigenetic factors, genetic variants and brain phenotypes in humans. He also received training in Constructivist Psychology and Psychotherapy. Luca has joined the Lieber Institute in the spring of 2012 as a visiting scientist first and then as a postdoctoral fellow. In 2018, he was the recipient of the Andrea Poretti award.

Selected Publications

Selected Publications

Blasi G, Napolitano F, Ursini G, Taurisano P, Romano R, Caforio G, Fazio L, Gelao B, Di Giorgio A, Iacovelli L, Sinibaldi L, Popolizio T, Usiello A, Bertolino A. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci U S A 2011,108:1158-63.

Ursini G, Bollati V, Fazio L, Porcelli A, Iacovelli L, Catalani A, Sinibaldi L, Gelao B, Romano R, Rampino A, Taurisano P, Mancini M, Di Giorgio A, Popolizio T, Baccarelli A, De Blasi A, Blasi G, Bertolino A. Stress-related methylation of the COMT Val158 allele predicts human prefrontal cognition and activity. The Journal of Neuroscience 2011, 31:6692-8.

Recommended in Faculty Opinions: https://facultyopinions.com/prime/10760960

Commentary in:

– Wiers CE. Methylation and the human brain: towards a new discipline of imaging epigenetics. Eur Arch Psychiatry Clin Neurosci. 2012;262:271–273;

Punzi G, Ursini G, Shin JH, Kleinman JE, Hyde TM, Weinberger DR. Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA Molecular Psychiatry. Molecular Psychiatry 2014 Oct,19(10):1057-9.

Recommended in Faculty Opinions: https://facultyopinions.com/prime/718404638

Yoon KJ, Nguyen HN, Ursini G, Zhang F, Kim NS, Wen Z, Makri G, Nauen D, Shin JH, Park Y, Chung R, Pekle E, Zhang C, Towe M, Hussaini SM, Lee Y, Rujescu D, St Clair D, Kleinman JE, Hyde TM, Krauss G, Christian KM, Rapoport JL, Weinberger DR, Song H, Ming GL Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity. Cell Stem Cell 2014 Jul 3,15(1):79-91.

Ursini G, Cavalleri T, Fazio T, Angrisano T, Iacovelli L, Porcelli A, Maddalena G, Punzi G, Mancini M, Gelao B, Romano R, Masellis R, Calabrese F, Rampino A, Taurisano P, Di Giorgio A, Keller S, Tarantini L, Sinibaldi L, Quarto T, Popolizio T, Caforio G, Blasi G, Riva MA, De Blasi A, Chiariotti L, Bollati V, Bertolino A BDNF rs6265 methylation and genotype interact on risk for schizophrenia. Epigenetics 2016 Jan 2,11(1):11-23.

Rampino A, Taurisano P, Fanelli G, Attrotto M, Torretta S, Antonucci LA, Miccolis G, Pergola G, Ursini G, Maddalena G, Romano R, Masellis R, Di Carlo P, Pignataro P, Blasi G, Bertolino A*. A Polygenic Risk Score of glutamatergic SNPs associated with schizophrenia predicts attentional behavior and related brain activity in healthy humans. Eur Neuropsychopharmacol. 2017 Sep;27(9):928-939.

Recommended in Faculty Opinions: https://facultyopinions.com/prime/727752684

Rutten BPF, Vermetten E, Vinkers CH^, Ursini G^, Daskalakis NP^, Pishva E, de Nijs L, Houtepen LC, Eijssen L, Jaffe AE, Kenis G, Viechtbauer W, van den Hove D, Schraut KG, Lesch KP, Kleinman JE, Hyde TM, Weinberger DR, Schalkwyk L, Lunnon K, Mill J, Cohen H, Yehuda R, Baker DG, Maihofer AX, Nievergelt CM, Geuze E, Boks MPM. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol Psychiatry. 2018 May;23(5):1145-1156. [NB: ^: equal contributions]

Mentioned on The Atlantic:

https://www.theatlantic.com/science/archive/2018/05/twin-epigenetics/560189/

Chen Q*, Ursini G *, Romer AL, Knodt AR, Mezeivtch K, Xiao E, Pergola G, Blasi G, Straub RE, Callicott JH, Berman K, Hariri AR, Bertolino A, Mattay VS, Weinberger DR. Schizophrenia Polygenic Risk Score Predicts Mnemonic Hippocampal Activity. Brain. 2018 Apr 1;141(4):1218-1228. [*equal contribution] Video abstract for Brain.

Press release: https://scholars.duke.edu/display/pub1314147

Punzi G, Bharadwaj R, Ursini G. Neuroepigenetics of Schizophrenia (Chapter Nine of the Volume “Neuroepigenetics of Mental Illness”). Progress in Molecular Biology and Translational Science 2018;158:195-226.

Ursini G, Punzi G, Chen Q, Marenco S, Robinson JF, Porcelli A, Hamilton EG, Mitjans M, Maddalena G, Begemann M, Seidel J, Yanamori H, Jaffe AE, Berman KF, Egan MF, Straub RE, Colantuoni CC, Blasi G, Hashimoto R, Rujescu D, Ehrenreich H, Bertolino A, Weinberger DR. Convergence of placenta biology and genetic risk for schizophrenia. Nature Medicine 2018 Jun;24(6):792-801.

Press release:

https://www.libd.org/new-study-finds-placenta-health-affects-risk-of-schizophrenia/

Mentioned on:

Ursini G^, Punzi G^, Langworthy BW, Chen Q, Xia K, Cornea EA, Goldman BD, Styner MA, Knickmeyer RC, Gilmore JH*, Weinberger DR*. Placental genomic risk scores and early neurodevelopmental outcomes. Proceedings of the National Academy of Sciences (PNAS). February 16, 2021 118 (7) e2019789118. [^: equal contributions]

Press release:

https://news.unchealthcare.org/2021/02/specific-genes-in-placenta-may-predict-size-of-babys-brain- and-risk-for-schizophrenia/

Mentioned on:

https://bobkolker.medium.com/the-seed-of-mental-illness-might-be-planted-before-birth-9cecbe1df440

Namkung H, Yukitake H, Fukudome D, Lee BJ, Ursini G, Lam S, Kannan S, Saito A, Niwa M, Sharma K, Zandi P, Jaaro-Peled H, Ishizuka K, Chatterjee N, Huganir R, Sawa A. The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder. Neuron. 2022 Nov 9;S0896-6273(22)00964-3.

Ursini G*, Di Carlo P, Mukherjee S, Chen Q, Han S, Kim J, Deyssenroth M, Marsit CJ, Chen J, Hao K, Punzi G,  Weinberger DR*, Prioritization of Placental Schizophrenia Risk Genes. Nature Communications, 2023 May 15;14(1):2613.  [*Co-corresponding authors]

Press release:

https://www.libd.org/new-study-finds-the-placenta-not-only-the-brain-plays-a-central-role-in-genetic-risk-of-schizophrenia/

Commentaries in:

  • McCarthy M, Intersection of schizophrenia genetics and placental complications. Nature Medicine. 2018 24: 707–8.
  • Wood H. Placental gene expression linked to schizophrenia risk. Nature Reviews Neurology. 2018 Jul;14(7):381.

Punzi G*, Ursini G, Chen Q, Radulescu E, Tao R, Huuki LA, Di Carlo P, Collado-Torres L, Shin JH, Catanesi R, Jaffe AE, Hyde TM, Kleinman JE, Mackay TFC, Weinberger DR*. Genetics and brain transcriptomics of completed suicide. The American Journal of Psychiatry. 2022 Mar;179(3):226-241.

Complete List of Published Work in MyBibliography:  

https://www.ncbi.nlm.nih.gov/myncbi/1luGfpehtKv5T/bibliography/public/

Team Members

Team Members

Jiyoung Kim, Ph.D., is a staff scientist in the U.R.S.INI lab. Her research interest is to identify the mechanisms through which genetic risk for schizophrenia converges with ELCs, prenatal and perinatal complications. Her research focuses mainly on the placenta. Modeling human trophoblast from patients and control groups, she is working to characterize whether patients affected with schizophrenia show phenotypic differences in differentiated trophoblast, syncytiotrophoblast, and extravillous trophoblast compared to unaffected controls. With this in vitro system, she also aims at investigating the effect of placental genomic predictors and placental genes associated with risk on placenta development and functions and the possible impact on human brain development of regulating secreted factors. Jiyoung earned her BS, MS, and Ph.D. from Konkuk University, Seoul, Korea, where she studied germline development in C. elegans animal genetic model system. Using germline defective mutants that generate no offspring, she identified the responsible gene for the sterility by forward and reverse genetics, and she found the mechanism underlying the role played by this gene in oocyte maturation. She was also a postdoctoral fellow in the National Institutes of Health, where she studied the post-transcriptional gene regulation by long noncoding RNAs in human cancer cells. Before joining the Lieber Institute, Jiyoung worked as a scientist in Elixirgen Therapeutics, participating in IND drug development for age-related diseases and an RNA-based COVID-19 vaccine. 

Bonna Sheehan joined the Lieber Institute for Brain Development (LIBD) in June 2022 and is currently characterizing iPSCs, TSCs, STBs, and EVTs to identify a link between placental development and risk of neurodevelopmental disorders in Dr. Gianluca Ursini’s lab. Previously, she worked in Dr. Jennifer Erwin’s lab at LIBD where she characterized iPSC and ventral forebrain organoid models of X-linked Dystonia Parkinsonism (XDP) to uncover mechanisms of pathogenesis and identify therapeutic targets. Bonna earned her B.S. degree in Cell and Molecular Biology with a Minor in Chemistry from West Chester University of Pennsylvania. There, she conducted research on auto-inflammatory diseases under Dr. James Pruitt in a medicinal chemistry laboratory, determining therapeutic value of synthesized small molecule inhibitors to the macrophage migration inhibitory factor (MIF) protein. After graduation, she began working for the Center for Inherited Disease Research (CIDR) at the Johns Hopkins University School of Medicine where she prepared and sequenced DNA samples for large-scale projects, utilizing and troubleshooting manual and advanced automated liquid handlers. Bonna is excited for the future of her work, and she hopes to continue to push the boundaries of her field.

Sreya Mukherjee, Ph.D., is a postdoctoral fellow working in the U.R.S.INI lab since April 2021. She analyzes transcriptomic data from the placenta and brain to unravel tissue-specific etiopathogenetic mechanisms linked with genomic risk for schizophrenia, using various bioinformatics methods and tools. Sreya received an M.S. in Bioinformatics from The Johns Hopkins University, Baltimore, and a Ph.D. from the University of South Florida, Tampa, in Computational Medicinal Chemistry. During her Ph.D., she has been designing different structure-based drug targets for various diseases. Sreya hopes, with her work, to unlock research answers that can help people.

Jisu Ha, Ph.D., is a staff scientist in the U.R.S.INI lab since February 2023. He is currently working on implementing newly developed algorithms to analyze single-cell genomic data from the brain and placenta and data from longitudinal study cohorts. His research interests include epigenomics, transcriptomics, and machine learning. He completed his Ph.D. degree in the Genetics, Genomics and Bioinformatics program at the University of California, Riverside. He carried out postdoctoral training at the National Institute of Aging of the NIH, and at the Dept. of Psychiatry and Behavioral Sciences of the Johns Hopkins School of Medicine.

Pasquale Di CarloM.D., Ph.D. is an active collaborator of the U.R.S.INI lab. While completing his residency in Psychiatry and Ph.D. program at the University of Bari “Aldo Moro,” he joined the Lieber Institute for Brain Development in the winter of 2018 as a Visiting Scientist. Throughout his training, he acquired broad expertise in psychiatry, imaging genetics and computational neuroscience, which he directed to the investigation of psychiatric disorders, particularly schizophrenia. Specifically, he set off the study of a co-expression network based on post-mortem microarray and RNA sequencing data to unravel the genetic and molecular underpinnings of schizophrenia etiology. He is primarily interested in developing predictive probabilistic models to translate post-mortem data into in vivo findings. As a Visiting Scientist at the Lieber Institute, he has built on these disciplines, mastering new skills in molecular biology and data science to complete his training as a young scientist. He is currently working as a psychiatrist in the Department of Mental Health of Sondrio (Milan, Italy). He is continuing to work on characterizing the molecular context of neurodevelopmental genes in terms of brain Spatio-temporal co-expression patterns and at the fetal-placental interface.

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Research Associate–Functional Genomics

Staff Scientist I–Functional Genomics

Research

Research

Schizophrenia and neuropsychiatric disorders do not initiate in early life, but trajectories of risk for neurodevelopmental alterations do. The U.R.S.INI lab has the main objective of studying the intersection between genes and the environment affecting these early risk trajectories. The lab’s name is also an acronym for “Unit for Research on how Schizophrenia INItiates.”

Defining the context where neurodevelopmental genes work

How do genes critical for neurodevelopment work? And where? And when? Is the etiopathogenesis of schizophrenia and other neurodevelopmental disorders (NDDs) only related to genetic risk in the fetal and/or adult brain?

Because schizophrenia and other NDDs are highly heritable, but complications during prenatal and perinatal life (Early Life Complications, ELCs) represent the most common environmental risk factor for these disorders in the offspring, we are investigating the convergence of placenta biology and genomic risk for NDDs. Our work indicates that genomic risk for schizophrenia interacts with ELCs. The liability of schizophrenia explained by genomic risk is much higher in individuals with a history of ELCs than when ELCs are absent. The genes in the schizophrenia risk loci are very highly expressed in the placenta, particularly in placentae from complicated pregnancies and male offspring. Indeed, by computing a measure of placental genomic risk for schizophrenia based on gene expression in the placenta, we have found that placenta gene expression may mediate the interaction between genomic risk and ELCs on case-control status (Ursini et al., Nature Medicine 2018). In a follow-up of this work, the placental genomic risk for schizophrenia is also associated with early neurodevelopmental trajectories of risk, as shown by its association with neonatal brain volume and developmental scores at one year of age, particularly in male individuals (Ursini, Punzi, et al., PNAS 2021).

We are now using multiple approaches to define the placental biological processes linked with genomic risk for NDDs and relevant for brain development:

  • Detection of placental mediators of risk: By analyzing transcriptomic data from human placentae, we are searching for the gene isoforms in the placenta that mediate the relationship between genomic risk, ELCs and maternal stress, and trajectories of risk for NDDs. In particular, we are implementing computational approaches leveraging the relationship between genetic variation and gene expression in the placenta to identify the gene isoforms whose altered expression in the placenta may have a causative role on risk trajectories for schizophrenia and NDDs. Similar parallel analyses in the fetal brain allow us to define placental-specific effects.
  • In vitro study of placental phenotypes associated with genomic risk: We are differentiating induced pluripotent stem cells (iPSCs), derived from fibroblasts of neurotypical controls and patients with schizophrenia, in trophectoderm, trophoblast stem cells, syncytiotrophoblasts, and extravillous trophoblasts. This research aims to identify whether genomic risk for schizophrenia and the placental mediators of risk defined by the transcriptomic analyses described above are associated with possible alterations of placental development and physiology, which may affect brain development.

This research is designed to understand neurodevelopment and advance novel specific approaches for prenatal and postnatal prevention of schizophrenia and NDDs, aimed respectively at preserving the health of the mother-fetus-placenta triad and rescuing physiological neurodevelopment in high-risk infants. Because the certainty of developing schizophrenia and NDDs is not fixed at birth, characterizing and detecting early altered trajectories may be crucial to understanding the factors and the mechanisms contributing to the transition from risk to actual disease or the canalization toward healthy development of the brain.

As individuals experience different and dynamic environments starting very early in life, their genes do not behave like fixed entities with unchanged levels of expression; they are instead flexible systems responding to various contexts. By combining post-mortem data and cellular cultures at the molecular levels, we are also studying divergent RNAs, a class of transcripts contributing to a large amount of noncoding RNAs expressed in transcriptionally active cells. They might provide a compelling mechanism for the fine-tuning regulation of protein-coding genes, essential for brain development and activity. In collaboration with the developmental plasticity team, we are functional characterizing divergent transcription in the BDNF locus.