The Sever Laboratory
Basic Scientific Research With Clinical Relevance
Despite hundreds of millions of people losing kidney function world-wide every year, no kidney-specific therapeutics exist. The current treatments for kidney loss, dialysis and transplant, significantly diminish quality of life and life span. The goal of our research is to elucidate the molecular mechanisms of kidney diseases to identify druggable pathways and develop new therapeutics. We primarily focus on the role of the GTPase dynamin in regulating actin cytoskeleton dynamics and clathrin-mediated endocytosis. Disregulation of both of these processes has been implicated in the loss of kidney-specific cells called podocytes that are required for kidney function. Gaining a better understanding of podocyte pathobiology will lay the groundwork to cure kidney disease.
Dyamin is a founding member of a superfamily of large GTPases that exist in multiple oligomerization states. Dynamin is best known for its role in clathrin-mediated endocytosis. Its ability to self-assemble into helices on lipid templates in vitro has led to the paradigm that dynamin directly executes the fission reaction in which coated pits are freed from the plasma membrane. We have identified regulation of the actin cytoskeleton as an additional and distinct role for dynamin oligomerization in podocytes and other cell types. By using classic cell biology, biochemistry, single molecule imaging, and animal models, we are establishing novel paradigms for dynamin function, the actin cytoskeleton, and endocytosis in healthy and injured kidney cells.
The Sever lab is a welcoming and highly interactive environment. Post-doctoral fellows and research technicians share expertise, reagents, and ideas to reach their common goal of understanding how dynamin regulates the actin cytoskeleton in healthy and diseased tissue. We are always looking for energetic and accomplished post-doctoral fellows with expertise in molecular biology, biochemistry, and/or biophysics.
The establishment of distinct, cell-type specific, cellular features, including cell polarity, involve signaling cascades, membrane trafficking, and cytoskeletal dynamics, all of which need to be highly coordinated and regulated. We seek to understand the role of the GTPase dynamin as one of the major coordinators of multiple cellular processes including endocytosis, actin cytoskeleton dynamics, as well as microtubule dynamics, in healthy and injured cells.
In 2010 we identified direct interactions between dynamin and actin filaments and we have since shown that the dynamin oligomerization cycle plays a direct role in regulating actin polymerization and crosslinking of actin filaments. These interactions have since been implicated in highly diverse cellular processes including endocytosis, the formation of lamellipodia, filopodia invadopodia, and growth cones in neuronal cells. All these processes are driven by the association of distinct actin structures with the plasma membrane. We now seek to identify the molecular mechanisms by which dynamin establishes such diverse cellular processes. Utilizing biochemical and cell biology assays, and total internal reflection fluorescence (TIRF) single-molecule imaging, we plan to elucidate the mechanism by which dynamin regulates actin and microtubule dynamics. We use kidney specific cells named podocytes as an experimental model system to study the role of dynamin with regard to endocytosis, the actin cytoskeleton, and microtubule dynamics. Podocytes are terminally differentiated cells that form the filtration barrier in the kidney. Damage or loss of podocytes is an early symptom of many kidney diseases as structural integrity of the podocyte actin and microtubule cytoskeleton is critical for its proper function. Better understanding podocyte pathobiology has lead to the establishment of novel paradigms with regard to role of dynamin in the cell and has the potential to pave the way for developing a cure for kidney diseases.
This photo shows the structure of podocytes in mice expressing dynamin mutant R725A, which increases dynamin’s propensity to oligomerize into higher-order structures such as rings. Dynamin oligomerization has been implicated in clathrin-mediated endocytosis, but here we show for the first time that its oligomerization plays an essential physiological role by directly regulating the actin cytoskeleton. This, in turn, drives the formation of foot processes that are significantly longer than those in wild-type animals as well as those in animals before Doxycycline treatment (used to drive expression of DynR725A). It is very rare to see such a dramatic effect on the length of the foot processes (FPs) since dominant-negative mutations of diverse proteins expressed in podocytes typically result in the loss of FPs. It should be noted that this particular dynamin mutant (DynR725A) has been published by Dr. Sever back in 1999 in Nature (Sever et al, Nature 1999). This mutant suggested that dynamin is a regulatory GTPase and not a pinchase. As you can see, this mutant has a long history.
We are also interested in the role of dynamin in clathrin-mediated endocytosis. The classical view of dynamin holds that it acts as a mechanochemical enzyme or “pinchase,” severing vesicles from the plasma membrane. Our work suggests an alternative model in which dynamin is a regulatory GTPase, orchestrating formation of clathrin-coated vesicles. In this view unoligomerized dynamin recruits additional proteins that drive formation of fully invaginated coated pits and subsequent budding of free vesicles. Our latest studies suggest that dynamin oligomerization may play an indirect but global role in endocytosis through regulation of actin.
This image shows localization of dynamin (labeled with black dots) on clathrin coated vesicles (labeled ‘V’) in foot processes of mice.
Chronic kidney disease, which is loss of kidney function over time, affects hundreds of millions of people worldwide. It is often associated with the appearance of significant amounts of high-molecular-weight plasma proteins such as albumin in the urine (termed proteinuria), a symptom of a compromised glomerular filtration barrier. Chronic kidney disease can occur due to genetic mutations in “house keeping genes” such as a-actinin 4, or more often as a secondary effect of diabetes and hypertension. Irrespective of genetic or disease-based causes, podocyte injury underlies loss of kidney function. Podocytes are terminally differentiated cells of the glomerulus, which consist of a cell body, primary microtubule-driven membrane extensions, as well as secondary actin-based membrane extensions called foot processes. Sustained dis-regulation of the actin cytoskeleton in foot processes ultimately leads to podocyte loss. We have shown that pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Our study established the first successful targeting of the actin cytoskeleton dynamics in foot processes and in the whole organism. Current research in the lab focuses on interplay between actin, microtubule dynamics, and endocytosis, and the role of dynamin in coordinating these processes in podocytes. We are also examining role of these processes in polarized epithelial cells of renal tubules. Cells of the renal tubules are often injured during anti-cancer therapies, resulting in acute loss of kidney function. The immerging view of kidney disease is that regardless of the injury (diabetes, hypertension, anti-cancer drugs, genetics), the whole organ is somehow affected. Our current challenge is to establish comprehensive understanding of the kidney injury as a whole organ, instead of focusing only on distinct cell types within the organ (podocytes vs epithelial cells).
This image shows dynamin (green) localization at actin filaments and focal adhesions in cultured differentiated mouse podocytes. The actin filaments and focal adhesions are labeled in red.
Florescence lifetime image microscopy (FLIM) was used to identify localization of dynamin oligomers in cultured podocytes (red signal).
As is the case with kidney diseases, the identification of therapeutic targets based on novel mechanistic studies is urgently needed for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and prion diseases. Given our insights regarding the role of the actin cytoskeleton and dynamin in the kidney, we are currently testing our hypothesis that targeting the actin cytoskeleton of dendritic spines may preserve and even reverse early signs of neurodegeneration. The Sever laboratory is striving to establish a unique environment with MGH and HMS where focusing on the basic cellular processes such as dynamin, actin, microtubules ,and endocytosis, we can elucidate common and cell type specific molecular mechanisms that govern highly diverse diseases.
Actin based foot processes of podocytes (left image) are structurally similar to actin based dendritic spines in neurons (right image).
Principal Investigator, Associate Professor of Medicine
Postdoctoral Research Fellow, The Scripps Research Institute
Ph.D. in Biochemistry, Zagreb University & Visiting graduate student, Yale University
M.S. in Molecular Biology, Zagreb University
B.S. in Molecular Biology, Zagreb University
Postdoctoral Research Fellow, Harvard Medical School and the Massachusetts General Hospital
Postdoctoral Research Fellow, Department of Life Science, Sookmyung Women’s University
Ph.D. in Biomedical Gerontology, Hallym University
M.S. in Biomedical Gerontology, Hallym University
B.S. in Microbiology, Hankuk University of Foreign Studies
Postdoctoral Research Fellow
Postdoctoral Research Associate in Chemical Biology, State University of New York at Binghamton
Ph.D. in Chemistry, State University of New York at Binghamton
M.S. in Applied Microbiology, Vellore Institute of Technology University
B.S. in Biochemistry, Microbiology, and Botany, Bangalore University
Research Scientist, Brandeis University, Rosenstiel Basic Medical Sciences Research Center
Research Associate, University of Pennsylvania
Postdoctoral Researcher, Boston University School of Medicine
Ph.D. in Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences
M.S. in Organic Chemistry, Warsaw University of Technology
B. Eng. in Organic Chemistry, Warsaw University of Technology
B.S. in Molecular Biology and Biochemistry, and the College of Integrative Sciences, Wesleyan University
B.S. in Biology, College of Natural Sciences, University of Massachusetts Amherst
MARINA KASAIKINA, PH.D. (2013-2015)
Postdoctoral Fellow at Dana Farber Cancer Institute
Postdoctoral Research Fellow, Tufts University
Ph.D. in Biochemistry, University of Nebraska-Lincoln
B.S./M.S. in Bioorganic Chemistry, Moscow State University
VALENTINA SHCHEDRINA, PH.D. (2012-2014)
Scientist at BioVision
Postdoctoral Research Fellow, Brigham & Women’s Hospital
Postdoctoral Research Fellow, University of Nebraska-Lincoln
Ph.D. in Biochemistry, Moscow State University
M.S. in Chemistry, Moscow State University
B.S. in Chemistry, Moscow State University
MIROSLAV SEKULIC, M.D./PH.D. (2012-2013)
Assistant Professor, Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center
Fellowship in Renal Pathology, Brigham And Women’s Hospital
Research Fellowship in Fabry Disease, University Of Bergen
Residency in Anatomic and Clinical Pathology, University Of Minnesota Affiliated Hospitals
M.D. University of Belgrade School of Medicine’
M.A. in Medical Sciences, Boston University School of Medicine
B.S. in Physiology & Neurobiology, University of Connecticut
SUMA YADDANAPUDI, PH.D. (2007-2012)
Senior Manager- Medical Affairs Training and Field Alignment at TESARO, inc.
Principal Scientist at Pfizer
Ph.D. in Pharmaceutical Sciences, University of Connecticut
B.S. in Pharmacy, Osmania University
SUBBULAKSHMI CHIDAMBARAM, PH.D. (2007-2008)
UGC Assistant Professor at Pondicherry Central University
Senior Scientist at Vision Research Foundation
ELISABETTA DEL RE, PH.D. (2003-2005)
Assistant Professor of Psychiatry at Harvard Medical School
Transitioning to Industry
M.S. in pharmaceutics, MCPHS University
B.S. in pharmaceutics, Wuhan Institute of Technology
Applying for Medical School
B.S. in Biology, Saint Michael’s College
Research Associate II at The Broad Institute of MIT and Harvard
Research Technician at Dana Farber Cancer Institute
B.S. Smith College
Research Associate at Massachusetts Institute of Technology
B.S. in Neuroscience, Brown University
EILEEN KAPPLES (2013-2015)
Went on to Medical School
B.S. in Biology, Georgetown University
JOANN CHANG (2011-2013)
Brown University Residence Program
Case Western Reserve School of Medicine
University of Michigan School of Law, J.D.
Cornell University, B.A.
Tufts University School of Medicine
Smith College, B.A
DAVID KO (2005-2007)
UC Riverside Medical School
Scientist, In Vivo Discovery at Editas Medicine
Ph.D. in Molecular, Cellular, and Developmental Biology, University of Colorado Boulder
SHARIF NANKOE (2004-2006)
Residency in Family Medicine and Community health at UMass Medical School
M.D. University of Vermont College of Medicine
THOMAS GILMORE (2003-2005)
Went on to Medical School
Associate Professor at Anna Maria College
Assistant Professor at CUNY York College
Postdoctoral Researcher at the US Geological Survey
Ph.D. in Molecular and Cellular Biology, University of Massachusetts, Amherst
BENJAMIN DELLARIPA, 2019
Summer Student (Tufts University)
HARSHA PALADUGU, 2018
Summer Student (Harvard University)
SOPHIA MCLANE, 2017
Summer Student (University of Virginia)
CRISTINA BARDITA, 2014
Visiting Scholar (Rush University)
KARINA THIEME, 2013
Visiting Scholar (University of São Paulo)
2009 Summer Student (University of Connecticut)
TIM MARINELLI, 2008
Summer Student (Williams College)
ELENA BUKANOVA, 2004
Summer Student (Brown University)
We are hiring! See below for available positions.
If you are a recent Ph.D. or M.D. Ph.D., are highly motivated, have a background in modern biology, biophysics (for single molecule work) or physiology, and a strong publication record, you are encouraged to apply for a post-doctoral position in the Sever lab.
The Sever lab accepts recent B.S. interested in pursuing carrier in science or medicine. The successful applicant is required to have a Bachelor’s degree in Molecular Biology, Biochemistry, Cell Biology, Neurobiology, Chemistry, or a related field. Some previous lab experience with molecular biology or chemistry is preferred, although all necessary techniques will be taught.
Interested candidates should send a cover letter, resume, and a list of three references to Prof. Sanja Sever, Ph.D. (firstname.lastname@example.org).
Celebrating Ben’s successful completion of the Harvard Summer Research Program in Kidney Medicine July 2019
Left to Right: Kamalika, Olivia, Sanja, Changkyu, Bradley, Agnieszka, Ben
The Sever Lab celebrating MGH being voted #1 best hospital in U.S. News and World Reports
Left to right: Changkyu, Garrett, Vincent, Eileen
By the water near our lab in Charlestown
Left to right: Changkyu, Eileen, Vincent, Marina, Garrett, Sanja
Lunch at Pier 6
Left to right: Marina, Changkyu, Vincent, Eileen, Garrett
Left to right: Miro, Changkyu, Amanda, Joann, Marina, Valentina, Sanja
Left to Right: Monica, Garret, Kamalika, Sanja, Sophia, Agnieszka, and Changkyu
Lab members and their significant others on the Brookline roof top
149 13th Street,
+1 (617) 724 8922
From the MBTA Green Line, go to North Station. Here, you may board the free MGH/Partners shuttle bus (located at the intersection of Causeway Street and Haverhill Street) to the Charlestown Navy Yard, MGH East Research Building 149. The Sever Lab is on the 8th floor. The shuttle goes every 15 minutes during working hours (less often on weekends and holidays).
From the MBTA Red Line, go to Charles/MGH. Here you may board the free MGH/Partners shuttle bus to the Charlestown Navy Yard, MGH East Research Building 149. The bus stops behind the MGH Jackson building and on Staniford St. behind the Whole Foods. The Sever Lab is on the 8th floor. The shuttle goes every 15 minutes during working hours (less often on weekends and holidays).
At the end of Storrow Drive, just beyond the MGH Main Campus, take a left onto the McGrath-O’Brien Highway. The Museum of Science will be on your left. At the first set of lights, proceed right onto the Gilmore Bridge, then at the next lights take a right onto Rutherford Avenue. Turn left at the second lights onto Chelsea Street. The Navy Yard and the U.S.S. Constitution will be on your right. Continue on Chelsea Street through three sets of traffic lights (about 1 mile). At the fourth set of lights take a right and the MGH East Navy Yard Research Building (Bldg. 149) will be one block away on the right. Take the first left to the MGH Parking Garage, which is connected to the Research Building by overhead walkways.
Take I-90 to Route 93 North through downtown Boston and over the Zakim/Bunker Hill Bridge. Take the Sullivan Square exit. Go right at the bottom of the ramp and take the second exit off the Sullivan Square rotary towards Charlestown (keep Schrafft building on your left). At the first intersection, take a left onto Medford Street. At the end of Medford Street, take a left and an immediate right into the Navy Yard. The MGH East Navy Yard Research Building (Bldg. 149) will be one block away on your right. Take the first left to the Parking Garage, which is connected to the Research Building by overhead walkways.
Once you have arrived please call us at (617) 724-8922. You will have to check in with Security before we can escort you to the lab, so please bring your driver’s license or other government-issued identification.