Chicago - 4:00 PM - 5:00 PM
Madesh Muniswamy, Ph.D.
Professor of Nephrology
University of Texas - San Antonio
The Muniswamy laboratory currently explores cutting-edge optical imaging-based methods to address major questions pertaining to explore the phenomenon referred as mitochondrial shape transition (MIST), a process that is independent of fission or fusion (Cell Reports 2018). With these observations, we currently are employing new pharmacologic tools to probe organellar communication and cell function. Our hope is to offer deeper insights behind inter-organellar communication that might be exploited to precisely treat various forms of disease.
BMG Seminar: Decoding the cancer genome one codon at a time and its therapeutic implications -Davide Ruggero, PhD
Chicago - 10:00 AM - 11:00 AM
Our research is centered on understanding translational control of gene expression in both normal health and disease, with a particular focus on cancer biology. Our research combines mouse genetics with genome-wide translational profiling, in-depth molecular biology, and pharmacology to systematically define the points of regulation, in cis and trans, by which the genome is selectively decoded into proteins in a cell- and tissue-specific manner. We have uncovered that a common denominator of multiple oncogenic pathways is their ability to directly control the core translation machinery of a cell, resulting in the rapid remodeling of mRNA translation programs that promote distinct hallmarks of cancer development, such as cell growth, metabolism, and increased motility. Our most recent findings delineate the in vivo requirements for a distinct threshold of the major cap-binding protein, eIF4E, in normal organismal development compared to those required for translating the cancer genome. We show that increased eIF4E activity is essential for cancer cell survival as distinct subsets of mRNAs that regulate the cancer cell oxidative response are marked by the presence of a novel, eIF4E-dependent cis-acting motif present in their 5 UTRs. I will also discuss a new link between translational nutrient availability to maintain metabolic fitness and health span in vivo. In particular, we are defining the role of translation regulation for the first time in the poorly understood molecular program underlying increased risk of cancer development associated with obesity. I will also discuss the generation of the first comprehensive systems-level analysis of the cancer translatome during cancer development in vivo that highlights a dichotomy in transcriptional vs. translational control of gene expression guiding key, select steps in cancer development and evolution. The immediate impact of our research has been the design of a new generation of compounds to target the aberrant translation machinery in cancer cells, which are currently in clinical trials, and may reflect a new frontier in cancer therapy.
Davide Ruggero, PhD
Professor, Department of Urology
Helen Diller Family Chair in Basic Cancer Research
University of California San Francisco
Chicago - 2:00 PM - 3:00 PM
Join us remotely via BlueJeans.
The Center for Autism and Neurodevelopment of Northwestern University Feinberg School of Medicine welcomes you to attend a lecture featuring:
Louis Pt ek, MD
John C. Coleman Distinguished Professor of Neurology
University of California, San Francisco
Sleep contributes to our physical and mental health, and sleep perturbation has been linked to many health conditions. However, understanding of the human circadian system was impossible until the recognition of extreme behavioral variants of the human circadian system. The Mendelian trait of familial advanced sleep phase (FASP) 20 years ago opened up the possibility of identifying human genes and mutations that regulate the human clock. We have been studying many FASP families to identify such genetic variant and to probe the in vitro and in vivo functional consequences of such variants. These studies have led to many novel insights into the human circadian clock. Our work over the last 20 years has now culminated with reported estimates of FASP prevalence that is much higher than anyone could have predicted before. The resource of human families is leading to identification of novel circadian genes.
Dr. Louis Pt ek has used the tools of human genetics in the study of patients with an impressive range of human phenotypes. He pioneered the field of Channelopathies which encompasses a large group of episodic/electrical disorders of muscle, heart, and brain. His earliest work focused a group of rare episodic muscle diseases he had proposed as models for more complex episodic/electrical disorders like cardiac arrhythmias and epilepsy. In an elegant set of papers, he systematically cloned and characterized all the genes causing a variety of familial periodic paralyses. All encode ion channels and work from his and other labs has shown that homologs of these are the cause of some forms of cardiac arrhythmias, epilepsy, and migraine headache. Subsequently, his group has done extensive work in characterizing the functional consequences of disease causing mutations.
To this point, Pt ek s work had focused on human diseases. In another line of work motivated by a family with an interesting phenotype, he has now embarked into the challenging field of behavioral genetics. He and his colleague, Ying-Hui Fu, study the genetics of human sleep phenotypes. Familial advanced sleep phase (FASP), is manifest as a lifelong trait of extremely early sleep times and early morning awakening (1 am 4 am). Pt ek and Fu have gone on to characterize mutations in a growing list of genes that underlie the phenotype in 15% of FASP families. Furthermore, they ve gone on to model human mutations in Drosophila and mice. In vitro and in vivo experiments focused on regions harboring the human mutations has led to novel insights in fine tuning of circadian period regulation by phosphorylation and other post translational modifications.
He serves on a number editorial boards including Neurogenetics, eLife, and the Journal of Clinical Investigation. He is a member of the National Academy of Medicine, the American Association of Arts and Sciences, and the National Academy of Science.
Chicago - 10:00 AM - 11:00 AM
Protein folding in the cell relies heavily on chaperones. Even though much has been learned about chaperones, particularly in regard to their co-chaperone and co-factor requirements, observing how chaperones bind to a wide range of substrate proteins and affect their folding has proven to be very difficult. This difficulty primarily comes from two sources: the functional complexity of chaperone machines, and the fact that chaperone substrates are almost always poorly defined mixtures of partially structured folding intermediates. We decided to embark on a chaperone discovery journey with the aim of finding chaperones that are simpler and more biophysically tractable than those currently studied. Ideally, these new chaperones should act on a substrate protein whose folding mechanism is already well characterized, so that we can
determine precisely how the chaperone is affecting the folding of the substrate. We thus developed genetic selections that directly link the stability of model folding proteins to increased antibiotic resistance in vivo. The folding biosensors that we have developed function in the bacterial periplasm and cytosol, and in yeast. These biosensors have allowed us to optimize protein folding and discover new chaperones we used the first of our discovered chaperones, Spy, as a model to delve deeply into chaperone biology and we now understand, in unprecedented detail, how this chaperone interacts with client proteins to facilitate their folding. We are following our chaperone discovery efforts into yeast with the aim of addressing the role that host factors play in amyloid formation, which is linked to a number of devastating
James C. Bardwell, PhD
Rowena G. Matthews Collegiate Professor, Department of Molecular, Cellular, and Developmental Biology
Professor, Department of Biological Chemistry
University of Michigan
Howard Hughes Medical Institute Investigator
Chicago - 12:00 PM - 1:00 PM
Title: 'Nucleic Acid Transactions by Helicases are Involved in Fundamentally Important Biological Processes
Speaker: Robert M. Brosh, Jr., PhD, NIH
Senior Investigator & Chief, Section on DNA Helicases
Laboratory of Molecular Gerontology
National Institute on Aging, National Institutes of Health
Host: Hank Seifert, PhD
Genetic mutations in a class of molecular motor proteins known as helicases are linked to a growing number of human disorders, indicating that these enzymes have vitally important roles during replication, DNA repair, recombination and transcription. My research team believes that defining the biochemical and cellular functions of helicases will help us understand molecular defects associated with chromosomal variability. The focus of our group is genetic diseases frequently associated with premature aging, cancer, and/or mitochondrial dysfunction arising from mutations in genes encoding DNA helicases that operate uniquely in pathways of DNA repair and the replication stress response. Topics of interest include the importance of helicases in the replication stress response, cellular homeostasis, immunity and DNA repair.
BMG Seminar: Immortal Hematopoietic Stem Cells and Their Regulation by DNA Methylation - Peggy Goodell, PhD
Chicago - 10:00 AM - 11:00 AM
The peripheral blood is composed of many different cell types which are constantly being replenished via hematopoietic stem cells (HSCs). When young, thousands of hematopoietic stem cells residing in the bone marrow are simultaneously regenerating the blood. Over the past few years, high throughput sequencing has revealed that as we age, one or a few stem cells start dominating blood production, resulting in a condition termed clonal hematopoiesis , or CH . CH represents blood production from immortal stem cells that outcompete their normal counterparts. CH is driven by somatically acquired mutations in around 20 genes which confer a selective advantage over time. The gene encoding DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in CH, indicating that loss of its function confers longevity on the stem cell, even as it puts the host at risk for age-associated diseases such as leukemia. Dr. Goodell will discuss some of the cellular and molecular mechanisms that drive expansion of HSCs with DNMT3A and other CH-associated mutations.
Peggy Goodell, PhD
Professor, Department of Pediatrics
Professor, Department of Molecular and Human Genetics
Vivian L. Smith Chair in Regenerative Medicine
Baylor College of Medicine
BMG Seminar: Metabolic control of cell growth through the PI3K-mTOR signaling network - Brendan Manning, PhD
Chicago - 10:00 AM - 11:00 AM
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of nutrient metabolism. mTORC1 has the ability to integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The activation state of mTORC1 is tightly controlled through a small G protein switch involving the TSC1-TSC2-TBC1D7 complex (the TSC complex) and the Ras-related small G protein Rheb. The direct phosphorylation and inhibition of the TSC complex by the protein kinase Akt provides the major mechanistic link between growth factor signaling and mTORC1. Current evidence indicates that this signal is integrated with amino acid sensing pathways upstream of mTORC1 through independent spatial control over the subcellular localization of the TSC complex and mTORC1 to the surface of the lysosome. Our data indicate that both physiological growth signals and common oncogenic events in cancer activate mTORC1 through mechanisms leading to dissociation of the TSC protein complex from the lysosomal subpopulation of Rheb, which is required for mTORC1 activation.
Physiological and pathological activation of PI3K-mTOR signaling results in a shift from catabolic processes to anabolic biosynthetic processes. This pathway acutely responds to feeding and is also frequently and aberrantly activated in human cancers. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and tumors, including the de novo synthesis of proteins, lipids, and nucleotides. Research in our lab is focused on understanding the coordinated anabolic program downstream of PI3K-mTOR signaling and identifying metabolic vulnerabilities stemming from uncontrolled pathway activation that can be targeted in tumors. I will discuss our latest data on additional metabolic enzymes under control of the PI3K-mTOR network that contribute to an integrated metabolic program underlying cell growth in both normal and cancer cells.
Brendan Manning, PhD
Professor, Department of Genetics and Complex Diseases
Director of the Division of Biological Sciences
Director of the PhD Program in Biological Sciences in Public Health, Harvard Graduate School of Arts and Sciences
Harvard T.H. Chan School of Public Health
Chicago - 4:00 PM - 5:00 PM
Xin He, Ph.D.
Department of Human Genetics
University of Chicago
GWAS of neuropsychiatric diseases have identified many loci, however, causal variants often remain unknown. We performed ATAC-seq in human iPSC-derived neurons, and identified thousands of variants affecting chromatin accessibility. Scuh variants are highly enriched with risk variants of a range of brain disorders. We computationally fine-mapped causal variants and experimentally tested their activities using CRISPRi followed by single cell RNA-seq. Our work provides a frameowork for priortizing noncoding disease variants.
I will also describe a novel computational method to identify cancer driver genes. Our method provides a comprehensive model of how natural selection shape the mutational pattern of cancer genes. Applying it to TCGA, we identified 159 new potential driver genes. We experimentally validated mRNA methyltransferase METTL3 as a tumor suppressor gene.
Chicago - 12:00 PM - 1:00 PM
Title: Vibrio cholerae Responses to Antimicrobial Peptide Exposure
Speaker: Jyl Matson, PhD, University of Toledo
Host: Karla Satchell, PhD
Vibrio cholerae, the causative agent of epidemic cholera, encounters a variety of stressful conditions in the human gastrointestinal tract and in the aquatic environment. One of the many stresses that the bacteria encounter in the host is exposure to antimicrobial peptides on mucosal surfaces. Our ongoing studies aim to characterize newly identified proteins and pathways that contribute to bacterial survival in the presence of antimicrobial peptide stress. Related to this work, we have also identified antimicrobial peptides as an inducer of virulence gene expression in V. cholerae. Therefore, we also aim to elucidate the exact mechanism by which this signal is sensed and used to modulate gene expression.
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.