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: 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.


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.


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.”


Williamson V.,Virginia Commonwealth University | Kim A.,Virginia Commonwealth University | Xie B.,Lieber Institute for Brain Development | Omari McMichael G.,Virginia Institute of Psychiatric and Behavioral Genetics | And 2 more authors.
Briefings in Bioinformatics | Year: 2013

Deep sequencing has become a popular tool for novel miRNA detection but its data must be viewed carefully as the state of the field is still undeveloped. Using three different programs, miRDeep (v1, 2), miRanalyzer and DSAP, we have analyzed seven data sets (six biological and one simulated) to provide a critical evaluation of the programs performance. We selected these software based on their popularity and overall approach toward the detection of novel and known miRNAs using deep-sequencing data. The program comparisons suggest that, despite differing stringency levels they all identify a similar set of known and novel predictions. Comparisons between the first and second version of miRDeep suggest that the stringency level of each of these programs may, in fact, be a result of the algorithm used to map the reads to the target. Different stringency levels are likely to affect the number of possible novel candidates for functional verification, causing undue strain on resources and time. With that in mind, we propose that an intersection across multiple programs be taken, especially if considering novel candidates that will be targeted for additional analysis. Using this approach, we identify and performed initial validation of 12 novel predictions in our in-house data with real-time PCR, six of which have been previously unreported. © The Author 2012. Published by Oxford University Press.


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.


Calcaterra N.E.,Johns Hopkins University | Barrow J.C.,Johns Hopkins University | Barrow J.C.,Lieber Institute for Brain Development
ACS Chemical Neuroscience | Year: 2014

Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacological revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the standard for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chemical neuroscience will be considered along with its synthesis, pharmacology, drug metabolism, adverse events and dependence, clinical use, and regulatory issues. © 2014 American Chemical Society.


Mighdoll M.I.,Lieber Institute for Brain Development | Tao R.,Lieber Institute for Brain Development | Kleinman J.E.,Lieber Institute for Brain Development | Hyde T.M.,Lieber Institute for Brain Development | Hyde T.M.,Johns Hopkins Hospital
Schizophrenia Research | Year: 2015

The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical-neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial. © 2014 Elsevier B.V.


Chenoweth J.G.,Lieber Institute for Brain Development | McKay R.D.,Lieber Institute for Brain Development
Cell | Year: 2014

Finding a cell that reprograms in a nonstochastic manner without genetic manipulation has proven elusive. In this issue, Guo et al. report the identification of a cell defined by an ultrafast cycle whose progeny reprogram in a synchronous and rapid manner. © 2014 Elsevier Inc.


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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