CMPP Graduate Student Published in Nature Communications
Wednesday, October 24, 2018
Edward Ayoub, a Graduate student in the Cellular and Molecular Pharmacology and Physiology PhD Program and member of Archibald Perkins Lab published in Nature Communications on 10/12/2018. More information can be found on the Nature Website.
Paper Title & Abstract
EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
Edward Ayoub, Michael P. Wilson, Kathleen E. McGrath, Allison J. Li, Benjamin J. Frisch, James Palis, Laura M. Calvi, Yi Zhang & Archibald S. Perkins
Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the −14 kb upstream regulatory element (−14kbURE) at Spi1; knockdown of Spi1dampens the myeloid skewing. Furthermore, deletion of the −14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression.
CMPP Graduate Student Brandon Berry Wins Poster Award
Monday, September 24, 2018
The Wojtovich lab attended the Translational Research in Mitochondria, Aging, and Disease (TRiMaD) Symposium. A yearly event that brings together approximately 150-200 scientists from the Northeast to discuss the role of mitochondria in aging and disease.
8th Annual TRiMaD Website
Brandon Berry, Graduate Student in Wojtovich lab, was one of four recipients to win a poster award for his work entitled “Novel Optogenetic control of mitochondrial energetics rescues electron transport chain inhibition”
Edward Ayoub, CMPP graduate student in the laboratory of Dr. Archibald S. Perkins, was awarded an NRSA F31 beginning 8/1/18
Monday, July 23, 2018
Edward Ayoub - Recipient of a Two-Year Ruth L. Kirschstein National Research Service Award (NRSA)
Individual Predoctoral Fellowship (F31) August 1, 2018 – July 31, 2020
Thursday, July 19, 2018
Edward Ayoub, graduate student in the laboratory of Dr. Archibald S. Perkins was awarded a two-year Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship entitled, “Therapeutic Strategies for Anemia in 3q26 Rearranged Leukemia”.
According to the most recent NIH Cancer Statistics Review, leukemia, a cancer of blood cells, is the ninth most common type of cancer. Acute myeloid leukemia (AML) is an aggressive form of leukemia with high lethality (~75% of patients die 5 years after being diagnosed) characterized by anemia, and excessive proliferation of abnormal myeloid progenitor cells in the bone marrow (BM). Rearrangements of the chromosomal band 3q26 portend further reduction in survival, and lead to the overexpression of the oncogene Ecotropic Viral Integration Site 1 (EVI1). The severity of 3q26 rearranged AML, the lack of in-depth understanding of the role of EVI1 in leukemia, and the inadequate therapeutic strategies interested our lab and others to investigate EVI1 associated leukemogenesis. While previous groups used transplantation of BM virally transduced to overexpress EVI1, we are the first lab to recapitulate the effects of the 3q26 rearrangements in the mouse by establishing an inducible EVI1-overexpression model, which has provided us with new insights into the mechanisms by which EVI1 induces leukemia. We concluded using our in vivo and in vitro models that EVI1 causes myeloid expansion and blocks both erythropoiesis and lymphopoiesis. As an insight to the molecular mechanism, we previously documented that EVI1 binds to GACAAGATA, which overlaps with the binding site of the master regulator of erythropoiesis GATA-1. Additionally, our data indicate that EVI1 upregulates a previously published GATA-1 blocker, PU.1, and we showed that EVI1 binds to an enhancer upstream of PU.1 encoding gene (Spi-1). Thus, we hypothesize that EVI1 blocks erythroid differentiation by two mechanisms: 1) directly competing with GATA-1 for key genomic binding sites harboring EVI1/GATA-1 overlap motifs and 2) binding to Spi-1 enhancer and upregulating PU.1, which suppresses GATA1 function. We will investigate both hypothesized mechanisms using cutting edge techniques including ChIP-seq, ATAC-seq, and CRISPR under the training of my sponsor and collaborator. In order to translate the proposed mechanistic insights into clinical settings and therapeutic strategies, we will perform CRISPR library screening using an in vivo model to identify genes that reverse erythropoiesis blockage associated with EVI1-overexpression.
In summary, this fellowship will focus on investigating erythropoiesis blockage and resulting anemia that might explain the increased lethality associated with 3q26 rearranged leukemia, and It will unveil new therapeutic strategies that reverse the leukemia-associated anemia.
Isaac Fisher, 5th year graduate student in the lab of Alan V. Smrcka, won first place for his poster at the EB/ASPET meeting in San Diego
Monday, July 9, 2018
Congratulations to Isaac Fisher, a 5th year student in the laboratory of Dr. Alan V. Smrcka for receiving First Place in the Postbaccalaureate/Graduate Student category within the Division for Molecular Pharmacology! We applaud your contributions to ASPET’s 2018 Student Competition.
The winners of the awards for the ASPET Student Poster Competition were announced at the Division Mixer on Tuesday, April 24 at EB 2018 in San Diego.
Title: Hydrogen Deuterium Exchange Mass Spectrometry Reveals Distinct Activation States of PCLb by G-Protein
Authors: Isaac Fisher, Meredith Jenkins, Greg Tall, John Burke, and Alan V. Smrcka
See Awards on ASPET website
GSS Annual Poster Session - Travel Award Winners Announced
Thursday, June 7, 2018
Congratulations to our most recent GSS poster session Travel Award Winners!
Lara Terry, 3rd year student in David Yule Lab: 2nd place – Title: Effects of Missense Mutations on Inositol 1,4,5-trisphosphate Receptor Mediated Calcium Release.
Si Chen, 4th year student in Chen Yan lab: 3rd place – Title: PDE10A Inhibition and Deficiency Attenuate Pathological Cardiac Remodeling
Pharmacology Alumni Named Associate Dean
Friday, May 11, 2018
Jennifer Mathews, PhD has been named the Associate Dean for the Albany College of Pharmacy and Health Sciences - Vermont Campus.
Dr. Mathews earned her doctorate in Pharmacology from the University of Rochester in 2007, her field(s) of interest as a student were Neuropharmacology, Opioid receptors, Pain, Tolerance, Antinociception
Her responsibilities will include execution of the pharmacy program; supervision of faculty; campus operations; and coordination of the development, implementation, and assessment of initiatives that support the programs on the Vermont Campus, which also include a Master’s program in Pharmaceutical Sciences.
Congratulations to Dr. Mathews!Read More: Pharmacology Alumni Named Associate Dean
Brandon Berry Recipient of a two-year American Heart Association Predoctoral Fellowship & Professional Member of the AHA July 1, 2018 – June 30, 2020
Monday, April 23, 2018
Brandon Berry, graduate student in the laboratory of Dr. Andrew P. Wojtovich was awarded a two-year American Heart Association Predoctoral Fellowship entitled, “Optogenetic Control of Mitochondrial Function to Protect Against Ischemia Reperfusion Injury”.
Mitochondria are central mediators of cell death following the pathologic stress of ischemia reperfusion (IR) injury during heart attack or stroke. However, mitochondria can be targeted with specific interventions that inhibit cell death following IR. The mitochondrial protonmotive force (PMF) is coupled to ATP synthesis, and controls ion gradients and oxidative stress. Dissipation of the PMF in IR injury results in cellular damage and death. Interestingly, mild uncoupling of the PMF from ATP synthesis using low-dose protonophores protects against IR injury. It is unclear whether uncoupling triggers protective signaling, or if uncoupling itself is the effector of protection. Further, pharmacologic tools lack temporal and spatial control, obscuring when and where uncoupling is sufficient to protect against IR injury. Uncoupling mitochondria using optogenetics addresses the spatiotemporal challenge of using protonophores. Spatiotemporal control can determine if the mechanism of uncoupling confers protection before ischemia (preconditioning), during ischemia, during reperfusion, or after reperfusion (postconditioning). Overall, using our novel optogenetic tools, this project aims to test how precise, selective, reversible uncoupling is sufficient to elicit cellular responses that protect against IR injury.
Cindy Wang Wins America’s Got Regulatory Science Talent Competition
Monday, March 5, 2018
Xiaowen (Cindy) Wang, M.S., a graduate student in the Cellular and Molecular Pharmacology and Physiology PhD Program placed first in the 5th annual "America’s Got Regulatory Science Talent" competition for her proposal “Dr. Data: An Integrated Drug Repurposing Database for Identifying New Indications of FDA Approved Drugs”
To read more about Cindy’s proposal and the competition, please visit the CTSI Stories website.
This is how a brain gets hooked on opioids like it craves a candy bar
Friday, February 23, 2018
Eating a candy bar and injecting heroin each trigger a part of the brain that reinforces feeling good.
“Pleasure is pleasure,” said Jean Bidlack, a researcher at the University of Rochester Medical Center who is looking at a different way to treat opioid addiction.
While much of current thinking is focused on opioid receptors, Bidlack is going to look at how the neurotransmitter dopamine affects the desire for drugs.
“A candy bar will give you a little bit of dopamine release and give you pleasure,” said Bidlack, a professor of pharmacology and physiology. Regular ingestion can turn into a habit, but stopping isn’t likely to fundamentally change your life.
“Drugs of abuse like opioids will give you a very high dopamine level,” Bidlack said. “The brain adapts and says, ‘I want that high dopamine level all the time.’ And then when you don’t have it, that’s when the craving is very, very strong.”Read More: This is how a brain gets hooked on opioids like it craves a candy bar
Bidlack Receives NIH Grant For Opioid Addiction Research
Tuesday, February 13, 2018
From left: Dr. Janice Harbin, CEO at Anthony L. Jordan Health Center, Dr. Jean Bidlack, Mr. Michael Leary, CEO at Regional Primary Care Network, and Louise Slaughter.
A groundbreaking treatment for opioid addiction could come from local research. Monday, Congresswoman Louise Slaughter announced a $200,000 award from the NIH to a University of Rochester lab that is studying a possible new treatment for addiction.
Dr. Jean Bidlack of the University of Rochester Medical Center is involved in the research. “What I’m looking at is a hormone that has been shown in animals to reduce both the preference for sweets and alcohol by decreasing dopamine levels,” Dr. Bidlack explained. The money for the research of part of the federal budget approved last week.
The actual award is for 2 years, totaling of $385,000.
Congratulations Dr. Bidlack!