Lieber Institute for Brain Development

Baltimore, United States

Lieber Institute for Brain Development

Baltimore, United States
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Patent
Johns Hopkins University and Lieber Institute For Brain Development | Date: 2017-01-25

RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.


Patent
Johns Hopkins University and Lieber Institute For Brain Development | Date: 2015-03-20

RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.


Ma Y.,Beijing Normal University | Shamay-Tsoory S.,Haifa University | Han S.,Peking University | Zink C.F.,Lieber Institute for Brain Development
Trends in Cognitive Sciences | Year: 2016

Adaptation to the social environment is critical for human survival. The neuropeptide oxytocin (OT), implicated in social cognition and emotions pivotal to sociality and well-being, is a promising pharmacological target for social and emotional dysfunction. We suggest here that the multifaceted role of OT in socio-affective processes improves the capability for social adaptation. We review OT effects on socio-affective processes, with a focus on OT-neuroimaging studies, to elucidate neuropsychological mechanisms through which OT promotes social adaptation. We also review OT-neuroimaging studies of individuals with social deficits and suggest that OT ameliorates impaired social adaptation by normalizing hyper- or hypo-brain activity. The social adaption model (SAM) provides an integrative understanding of discrepant OT effects and the modulations of OT action by personal milieu and context. © 2015 Elsevier Ltd.


Murase S.,U.S. National Institutes of Health | Mckay R.D.,U.S. National Institutes of Health | Mckay R.D.,Lieber Institute for Brain Development
European Journal of Neuroscience | Year: 2014

Signal transducer and activator of transcription 3 (STAT3) dramatically increases during the first post-natal week, and supports the survival of mature hippocampal neurons. Recently, we reported that chronic elevation of excitability leads to a loss of STAT3 signal, inducing vulnerability in neurons. The loss of STAT3 signal was due to impaired Erk1/2 activation. While overnight elevation of activity attenuated STAT3 signal, brief low-frequency stimuli, which induce long-term depression, have been shown to activate STAT3. Here we investigated how STAT3 responds to depolarization in mature neurons. A brief depolarization results in the transient activation of STAT3: it induces calcium influx through L-type voltage-gated calcium channels, which triggers activation of Src family kinases. Src family kinases are required for phosphorylation of STAT3 at Tyr-705 and Ser-727. PTyr-705 is Janus kinase (JAK)-dependent, while PSer-727 is dependent on Akt, the Ser/Thr kinase. Both PTyr-705 and PSer-727 are necessary for nuclear translocation of STAT3 in these neurons. Chronic elevation of spontaneous activity by an A-type potassium blocker, 4-aminopyridine (4-AP), also induced the transient phosphorylation of STAT3, which after 4 h fell to basal levels despite the presence of 4-AP. These results suggest that phasic and chronic neuronal activation induce distinct molecular pathways, resulting in opposing regulation of STAT3 signal. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


News Article | October 14, 2016
Site: www.technologyreview.com

At the Lieber Institute for Brain Development in East Baltimore, dozens of brains from people who were diagnosed with post-traumatic stress disorder during their lifetimes are stored away in industrial-sized freezers intended to preserve vital tissue. The nonprofit research institute has amassed 81 of these PTSD brains—only a small portion of its nearly 2,000 total brains—in the six years it’s been open. It’s the biggest collection of post-mortem brains with a known diagnosis of PTSD. Scientists at Lieber are researching schizophrenia and related brain disorders and have an ambitious plan for the PTSD collection. They want to pinpoint the genetic variants that raise a person’s risk for developing PTSD after trauma and find targets in the brain to treat the disorder more effectively with drugs. Currently, people with PTSD are treated with a combination of talk therapy, or psychotherapy, and medications like antidepressants designed to treat symptoms of the disorder. About eight million adults in the U.S. have PTSD during a given year, according to estimates from the U.S. Department of Veterans Affairs. Globally, that number is much higher and includes not just combat soldiers but refugees, civilians exposed to war, and victims of domestic violence, assault, and sex trafficking. Studying post-mortem brains is essential to PTSD research, says Joel Kleinman, associate director of clinical sciences at Lieber. Much of what scientists and medical professionals know about PTSD has been gleaned from observing symptoms of the disorder. What’s unknown are the molecular and cellular changes that occur in the brains of people who develop PTSD. Kleinman says these changes are “distinctly human” and cannot be studied in animals. Kleinman and his colleagues will use RNA sequencing on the brains they’ve acquired to identify these changes. While the information in DNA is stable and dictates our biological traits, RNA helps carry out various tasks in cells, such as controlling gene expression. Gene expression, which can be measured with RNA sequencing, is important to researchers because the same gene may act in different ways under different circumstances. RNA tends to degrade in post-mortem tissue, so scientists at Lieber acquire the brains within hours of the donor dying and rush them back to the lab to chill on ice. This helps preserve the integrity of the tissue so that the RNA can be properly analyzed later. Andrew Jaffe, a researcher at Lieber, has also developed an algorithm that measures the degree of post-mortem RNA degradation to help his colleagues determine how much RNA is able to be analyzed in the brains. Lieber scientists have already done RNA sequencing on schizophrenia brains and published findings earlier this year about the discovery of a new protein linked to schizophrenia and related disorders, including depression, bipolar disorder, and attention deficit hyperactivity disorder. Researchers believe such proteins could be drug targets for these disorders. Once all the brains have been sequenced, they will cross-reference genetic variants found by other researchers to be associated with PTSD with their data to look for connections. The researchers will also do this with control brains to compare the results. Kleinman says he hopes the RNA sequencing will reveal the changes that need to happen to these genetic variants to cause the classic symptoms of PTSD. Kleinman and his team believe these brain changes, which involve proteins known as transcription factors, represent the holy grail for PTSD research: targets in the brain that could respond to drugs. But RNA sequencing alone will likely not be enough to lead to drug discovery. “The difficulty in RNA sequencing of post-mortem brains is determining whether the differences in expressions caused the PTSD, were the outcome of PTSD, or are the result or cause of something else entirely,” says Karestan Koenen, professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health. Koenen leads the PTSD working group within Psychiatric Genomics Consortium, an international collaboration of researchers, which is analyzing about 20,000 genetic samples from PTSD patients. In 2014, the consortium published data showing that more than 100 genetic variants are associated with schizophrenia risk. The consortium will do the same for its PTSD data within the next few years. That data will help scientists at Lieber narrow down which genetic variants it will focus on. While she says PTSD research is in a period of “accelerated discovery,” she acknowledges the long road ahead before a drug for this devastating disorder is found. “There’s a tension between the need and how quickly we can move,” she says. “But the caution is that we want to make sure we have solid results that can inform drug discovery.”


Hill J.L.,Lieber Institute for Brain Development | Martinowich K.,Lieber Institute for Brain Development
Current Opinion in Neurobiology | Year: 2016

Fear regulation is impaired in anxiety and trauma-related disorders. Patients experience heightened fear expression and reduced ability to extinguish fear memories. Because fear regulation is abnormal in these disorders and extinction recapitulates current treatment strategies, understanding the underlying mechanisms is vital for developing new treatments. This is critical because although extinction-based exposure therapy is a mainstay of treatment, relapse is common. We examine recent findings describing changes in network activity and functional connectivity within limbic circuits during fear regulation, and explore how activity-dependent signaling contributes to the neural activity patterns that control fear and anxiety. We review the role of the prototypical activity-dependent molecule, brain-derived neurotrophic factor (BDNF), whose signaling has been critically linked to regulation of fear behavior. © 2015 Elsevier Ltd.


Barrow J.C.,Lieber Institute for Brain Development
CNS and Neurological Disorders - Drug Targets | Year: 2012

Since the identification of Catechol-O-Methyltransferase (COMT) by Axelrod in 1957, many inhibitors of this enzyme have been reported. While COMT inhibition may be beneficial in a number of disease states, most of the effort over the years has been directed at boosting L-DOPA concentrations as adjunct treatment for Parkinson's disease. This review summarizes the major classes of COMT inhibitors, from early catechol and pyrogallol variants to bisubstrate inhibitors. The nitrocatechol substructure has proven to be a particularly productive scaffold, resulting in two marketed drugs and several improved drug candidates working their way through clinical trials. © 2012 Bentham Science Publishers.


Jaffe A.E.,Lieber Institute for Brain Development | Irizarry R.A.,Dana-Farber Cancer Institute
Genome Biology | Year: 2014

Background: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. However, blood is a heterogeneous collection of different cell types, each with a very different DNA methylation profile.Results: Using a statistical method that permits estimating the relative proportion of cell types from DNA methylation profiles, we examine data from five previously published studies, and find strong evidence of cell composition change across age in blood. We also demonstrate that, in these studies, cellular composition explains much of the observed variability in DNA methylation. Furthermore, we find high levels of confounding between age-related variability and cellular composition at the CpG level.Conclusions: Our findings underscore the importance of considering cell composition variability in epigenetic studies based on whole blood and other heterogeneous tissue sources. We also provide software for estimating and exploring this composition confounding for the Illumina 450k microarray. © 2014 Jaffe and Irizarry; licensee BioMed Central Ltd.


Patent
Lieber Institute For Brain Development | Date: 2016-01-29

The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinsons disease and/or schizophrenia.


Patent
Lieber Institute For Brain Development | Date: 2016-01-29

The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinsons disease and/or schizophrenia.

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