Research News: New Discovery from the Garcia-Marcos Laboratory
The Garcia-Marcos laboratory has discovered that heterotrimeric G-proteins, which are critical molecular switches in cellular communication processes, can trigger different responses in cells depending on the type of protein that activates them.
Heterotrimeric G-proteins are typically activated by G-protein-coupled receptors (GPCRs), which are the target for over one-third of drugs approved for use in the clinic. But G-proteins can also be activated by other proteins that are not GPCRs, a mechanism with important implications for human physiology and disease. The Garcia-Marcos laboratory has used an innovative approach to dissect and compare the consequences of G-protein stimulation by different activators, including GPCRs and various non-GPCR proteins. The approach leveraged a recently developed type of biosensors capable of detecting different forms of active G-proteins in living cells in real time. These were combined with engineered G-protein activator constructs that could be turned on at will with an exogenous synthetic chemical.
The main conclusion is that, contrary to previous beliefs, GPCR and non-GPCR activators elicit different forms of G-protein activation in cells. These findings have important implications in our understanding of pharmacologically actionable signaling hubs in cells, which could be leveraged to envision and design new therapeutic agents.
You can read the article here:
Garcia-Marcos M. Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators. Elife. 2021 Mar 31;10:e65620. PMID: 33787494 https://pubmed.ncbi.nlm.nih.gov/33787494/
Grant Award: Department of Defense, Discovery Award
Robert Mercer, a Postdoctoral Associate in the Harris Lab, was recently awarded a Discovery Award research grant funded by the Department of Defense. This two-year, $200,000 grant is entitled “ Identification of Receptors for TAR DNA-binding Protein 43 (TDP-43) That Mediate Cellular Uptake and Neurotoxicity ”. This project aims to identify the cellular receptors of the pathological TDP-43 assemblies found in the brains of patients with Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD), and Chronic Traumatic Encephalopathy (CTE). The identification of these receptors will provide novel therapeutic targets to combat these devastating and currently untreatable diseases.
Dr. Grishok Receives 2021 Shipley Pilot Grant
Dr. Alla Grishok, Associate Professor of Biochemistry has been awarded a 2021 Shipley Prostate Cancer Research Pilot Grant Award. She will act as coordinator of a multi-center, multi-PI initiative involving Dr. Christopher Heaphy (Department of Medicine), Dr. Joshua Campbell (Department of Medicine), and Dr. Rachel Flynn (Department of Pharmacology and Experimental Therapeutics, GSI) across Boston Medical Center (BMC) Pathology department, Shipley Prostate Cancer Research Center, BU-BMC Cancer Center, and Genome Science Institute (GSI) at BUSM.
The goals of this pilot research are: "to (1) identify coding and non-coding genomic alterations that are associated with more aggressive disease in Black men with prostate cancer and to (2) establish a pipeline that will integrate the genomic data with other biomarker measurements, such as the presence of circulating tumor DNA or alterations in the gut microbiome, and with the overall clinical outcomes in a large cohort of men". The success of this project may lead to better predictions of the severity of the disease in individual men and to informed selection of the appropriate treatment options in the future.
Research news: Methods to improve quantitative glycoprotein coverage
Most cell surface and extracellular matrix proteins are glycosylated as a mechanism driven by evolution that elaborates their adhesive interactions with binding partners. Such glycosylation occurs by biosynthetic reactions in the secretory pathway that gives rise to heterogeneity at each glycosylation site. This heterogeneity diversifies the range of interactions and therefore functions of glycoproteins. But, how can we understand the functional roles of glycoproteins if they are heterogeneous? Conventional proteomics methods have been adapted to quantify protein glycosylation heterogeneity, but understanding glycoprotein function requires improvements in sensitivity and selectivity. Chang and Zaia describe current methods of glycosylation quantification and show the promise of emerging glycoproteomics methods that employ data-independent analysis and ion mobility separations.
Grant Awards: Visualizing Alzheimer’s Disease
Ladan Amin an Instructor in the Harris laboratory was recently awarded a R03 research grant, funded by the National Institute on Aging (NIA). This two-year, $200,000 grant is entitled “Use of super-resolution microscopy to visualize the interaction between Alzheimer therapeutic antibodies and Aβ aggregates”. This project aims to identify the molecular mechanism of action of several different clinical antibodies by localizing them on single Aβ aggregates. This information will contribute significantly to understanding the basic biology of amyloid and its role in Alzheimer’s disease, and will provide a fuller picture of molecular mechanisms responsible for detoxifying oligomers and enhancing their clearance.
Franzblau Travel Award Recipients
The Dr. and Mrs. Franzblau Travel Award Committee is pleased to announce the winners of this year’s Myrna and Carl Franzblau Student Travel Awards. We had many deserving applications this year and were able to provide awards to four PhD students and four Postdoctoral Associates within the Department. The recipients and their advisors are listed below:
- Joe Kern (Varelas)
- Addie Matschulat (Varelas)
- Jarrod Moore (Emili)
- Matt Lawton (Emili)
- Tara Liyanage, Ph.D. (Costello)
- Nachen Yang, Ph.D. (Lau)
- Robert Mercer, Ph.D. (Harris)
- Zheng Zhu, Ph.D. (Lau)
These awards are made possible by the generosity of Dr. and Ms. Franzblau and will provide funds to defer the costs of travel for these trainees to present their research at a national/international scientific conference. This year’s award selection committee was comprised of members of the Biochemistry Department Dr. and Mrs. Franzblau Travel Award Committee (Barbara Schreiber (chair), Alla Grishok, and Steve Farmer). The Department thanks the selection committee for their careful consideration of all the applicants.
Congratulations!
Cohesin organizes the genome
A new review by first author Carlos Perea-Resa in the Blower lab was recently published in Trend in Cell Biology (Cohesin: Behind Dynamic Genome Topology and Gene Expression Reprogramming)
In spite of sharing the same DNA molecules, cells in our body show different shape and function as a consequence of differential gen
e expression. Studying how cells organize and read the instructions contained in the DNA is essential to fully understand organism development and the etiology of developmental diseases. A growing body of studies evidence the central role of the cohesin complex in both, organizing and reading genomic information. In this review published at Trends in Cell Biology, this article revises the most recent literature about how cohesin regulates gene expression. The article pays special attention to the role of cohesin in cell shifts across different stages of the cell cycle and during cell fate determination events in development. They also propose a scenario to explain the molecular etiology of Cornelia de Lange Syndrome, a developmental disease caused by cohesin disfunction on gene expression regulation.
Research discoveries: vascular progenitor differentiation and fibrosis
A new study from the Layne laboratory identified a novel mechanism for vascular adventitial remodeling. The paper, Aortic carboxypeptidase-like protein regulates vascular adventitial progenitor and fibroblast differentiation through myocardin related transcription factor A was published on February 17, 2021 in Scientific Reports.
The vascular adventitia, or outer layer of blood vessels contains numerous cell types including fibroblasts which are responsible for extracellular matrix production, adipocytes, inflammatory cells, and progenitor cells.
In response to vascular injury or disease adventitial firoblasts and progenitors become activated and secrete extracellular matrix proteins and become contractile leading to vessel remodeling. This study determined that the secreted protein Aortic carboxypeptidase-like protein (ACLP) repressed adventitial stem cell markers (CD34, KLF4) and increased collagen expression. Furthermore, ACLP enhanced the nuclear translocation of the transcriptional regulator myocardin-related transcription factor A (MRTFA) in adventitial cells. This study also determined that progenitor cells from MRTFA-null mice exhibited reduced smooth collagen and smooth muscle actin expression indicating that adventitial progenitor cell differentiation is regulated in part by the ACLP-MRTFA axis. Collectively these studies identified ACLP as a mediator of adventitial cellular differentiation, which may result in pathological vessel remodeling.
In addition to the first author Dahai Wang, collaborators on this project include Steve Farmer and Nabil Rabhi in the Department of Biochemistry and Shaw-Fang Yet from the Institute of Cellular and System Medicine in Taiwan.
This work was supported by NIH grants HL078869, DK117161, a grant from the American Heart Association, and the Evans Center for Interdisciplinary Research Fibrosis Affinity Research Collaborative.
Mosquitos and Small RNAs
BUSM researchers are now able to provide a new genomics resource that details the small RNA transcriptomes (gene expression) of four bio-medically important mosquito species.
This is the first study to provide a platform for biologists to compare the characteristics of these small RNAs between these four mosquitoes as well as the most widely used insects for genetic experiments, the fruit fly, Drosophila. Although previous studies looked at each of the individual mosquito species separately, this study is the first to allow comparisons between all four species.
“Although mosquitoes are related to Drosophila, they have very different genomes. In addition, mosquitos bite humans for blood meals that allow them to reproduce and but unfortunately allows serious human pathogens like viruses to infect us and cause diseases like yellow fever virus, dengue fever virus, zika virus and eastern equine encephalitis virus,” explained corresponding author Nelson Lau, PhD, associate professor of biochemistry.
The researchers obtained cell cultures and dissected samples of the mosquito species Anopheles gambiae, Culex quinquefasciatus, Aedes aegypti and Aedes albopictus. They extracted and purified the small RNA molecules, created libraries for high-throughput sequencing, and then developed a special bioinformatics platform to provide thorough genomic analysis of these small RNAs. They provide all this analysis in a public database website .
The four mosquito species have global impacts on human health. Anopheles is the major vector for the parasite causing malaria, but is not known to transmit many viruses. In contrast, Culex and Aedes mosquitoes are well known to pass viruses between humans during mosquito bites, but it is still unknown why there is this difference between mosquito species for this capacity to spread viruses.
According to the researchers this study will allow for better biochemical studies in mosquito cells. “If we can find weaknesses in the small RNA pathways of mosquitoes to make them more intolerant of viruses, perhaps they won’t be so able to pass the virus from biting one human to the next human victim.”
This study was a collaboration between the Lau lab in the Department of Biochemistry and the John Connor and Tonya Colpitts labs of the BU National Emerging Infectious Disease Laboratory (NEIDL) as well as many other mosquito biologists in the USA and the United Kingdom.
The findings appear online in the journal Genome Research.
Dr. Barbara Schreiber—Distinguished Faculty of the Month
The Faculty Affairs Office announced that Associate Professor of Biochemistry Barbara M. Schreiber, PhD, is September’s Distinguished Faculty of the Month.
Dr. Schreiber came to BUSM in 1975 as a graduate student in Microbiology and earned her PhD in Microbiology in 1981. She was a post-doctoral trainee in Clinical Microbiology at University Hospital from 1981-83 and a postdoctoral fellow in Biochemistry from 1983-87. Dr. Schreiber was appointed research assistant professor in 1987, research associate professor in 1997 and associate professor in 1999.
Dr. Schreiber currently serves as Director of Biochemistry graduate studies, Director of the Graduate Medical Sciences (GMS) PhD Program in Biomedical Sciences (PiBS), and course manager of the biochemistry class taught to first-year BU dental students and Oral Health Sciences MS students. Dr. Schreiber is the PI on a Burroughs Wellcome Fund Career Guidance in Training award and was co-PI on the NIH-funded BU’s BEST award, dedicated to broadening experiences in biomedical science training for our PhD students and post-doctoral trainees. She also serves as Assistant Dean for GMS Alumni Affairs.
The nomination states, “Dr. Schreiber orchestrated voluntary, weekly video conferences/meet-ups among the first-year Biomedical PhD (PiBS) students that we all found to be engaging and intellectually stimulating throughout the COVID-19 adjustment period.”
“Dr. Schreiber provided us with some personal interaction during a time of government mandated social isolation and general ambiguity from the earliest stages of the pandemic.”
Congratulations!
See original post: https://www.bumc.bu.edu/busm/2020/08/31/dr-barbara-schreiber-awarded-september-distinguished-faculty-of-the-month/