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Northwestern University Feinberg School of Medicine
Center for Genetic Medicine
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Events

Nov

25

SQE Distinguished Lecturer: Yi Zhang, PhD

Chicago - 10:00 AM - 11:00 AM

The Simpson Querrey Center for Epigenetics presents:

Yi Zhang, PhD
Fred Rosen Professor, Department of Genetics & Pediatrics, HMS & BCH
Investigator, Howard Hughes Medical Institute

Lecture Title: Mechanism and Function of a New Genomic Imprinting in Development & SCNT Reprogramming

Abstract: Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashion. Following fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci including imprinting control regions (ICRs). How parental chromatin becomes equalized and how ICRs escape from this reprogramming is largely unknown. Based on allelic chromatin accessibility and gene expression analyses, we identified a DNA methylation-independent, H3K27me3-depdendent imprinting mechanism. We demonstrate that H3K27me3-mediated genomic imprinting plays an important role in imprinted X-chromosome inactivation, placenta development, and somatic cell nuclear transfer reprogramming.





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Nov

25

Serotonergic Monitoring of Peripheral Inflammation: Clues to an Autism Treatment?

Chicago - 4:00 PM - 5:00 PM

Randy D. Blakely, Ph.D.
Executive Director of FAU Brain Institute
Professor of Biomedical Science
Florida Atlantic University

Epidemiological, post-mortem and gene network analyses have pointed to changes in inflammatory signaling pathways as a contribution to risk of autism. How such changes lead to alterations in brain development and function remain ill-defined. Previously, we identified an IL-1R activated p38 MAPK signaling pathway as central to the posttranslational control of serotonin signaling via modulation of presynaptic serotonin transporter (SERT) function, consistent with recent findings of significant expression of Il-1Rs by serotonin neurons. The possibility that an IL-1R/p38 MAPK/SERT signaling pathway might have disease relevance became of interest with our identification in subjects with autism of multiple, rare, hyperfunctional SERT coding variants that display constitutive p38 MAPK-dependent activation. With a knock-in mouse expressing the most common of these variants, SERT Ala56, we demonstrated elevated CNS serotonin clearance in vivo, and demonstrate changes in CNS and GI physiology and behavior consistent with constitutive-activation of SERT function. Recently, using brain penetrant, isoform-specific, p38 MAPK inhibitors, as well as conditional, serotonin neuron-specific elimination of p38 MAPK, we have been able to normalize multiple changes in these mice. Together, our studies point to the normal use of an IL-1R/p38 MAPK signaling pathway targeting SERT in serotonin neurons to modulate behavior in response to CNS and/or peripheral innate immune system activation. Inappropriate or excessive activation of this pathway during early life may contribute to one or more facets of autism that may be manipulated through pharmacological p38 MAPK inhibition.

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Dec

02

Direct Activation of Potassium Channels by Neurotransmitters and Ancient Medicines

Chicago - 4:00 PM - 5:00 PM

Geoffrey W. Abbott, Ph.D.
Professor of Pharmacology, Physiology and Biophysics
University of California Irvine

-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in vertebrate CNS. The canonical action of GABA is via binding to neuronal GABA receptors (GABARs) to induce hyperpolarization by intrinsic (GABAA/CRs) or extrinsic (GABABRs) ion channel activation. Voltage-gated potassium channels KCNQ2-5, especially KCNQ2/3 heteromers, generate the neuronal M-current, another important hyperpolarizing force. Here, we discuss our recent finding that GABA and related metabolites directly activate KCNQ2/3 channels, and KCNQ2/3-dependently hyperpolarizes cells, with sensitivity comparable to the most sensitive / / GABAARs. We identified the M-channel GABA binding site as KCNQ3-W265, a position conserved for >500 million years in deuterostome clades but absent in protostomes and in cardiac-expressed KCNQ1. M-channel activation is a novel, unexpected mechanism for physiological and therapeutic inhibitory actions of GABA and analogues. This work has led to further discoveries in KCNQ channel pharmacology, including isolation of a potent KCNQ channel activator from cilantro. We also found that activation of the vascular-expressed KCNQ5 is a common mechanism for a variety of genetically and culturally diverse hypotensive botanical folk medicines. The implications of this work will be discussed with respect to KCNQ channel physiology, pharmacology and drug discovery.

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Dec

06

BMG Distinguished Lecturer: Karen Vousden, PhD

Chicago - 10:00 AM - 11:00 AM

The Department of Biochemistry and Molecular Genetics presents:

Karen Vousden, PhD
Chief Scientist, CRUK
Group Leader, Francis Crick Institute, London

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Dec

09

Biology and Vulnerabilities of Circulating Tumor Cells

Chicago - 2:00 PM - 3:00 PM

Nicola Aceto, Ph.D.
SNSF Assistant Professor of Oncology
Cancer Metastasis Laboratory
Department of Biomedicine
University of Basel and University Hospital Basel

Abstract: Circulating tumor cells (CTCs) are key players in the metastatic process. With a combination of microfluidic technologies and single cell-resolution molecular analysis applied to breast cancer patients and mouse models, we gained fundamental insights into the biology and vulnerabilities of CTCs. For instance, we found that physical features such as their ability to form multicellular CTC clusters enable molecular changes that promote stemness and metastasis, allowing us to define new treatments to suppress metastatic spread, including the use of ion channel inhibitors. Further, we investigated CTC heterogeneity at the single cell level, revealing fundamental interactions that occur between CTCs and immune cells and that accelerate metastasis formation. Thus, our findings support a model whereby CTCs form multicellular aggregates with each other as well as with immune cells to expand their metastatic potential, providing a new rationale for targeting these interactions in breast cancer.

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