Department of Pathology News

Repairing nerve cell damage from multiple sclerosis

Tuesday, June 17, 2014

Dr. Bridget-Shafit Zagardo investigates how to repair nerve cell damage from multiple sclerosis.

















Each year multiple sclerosis (MS) strikes millions of young adults in the United States and worldwide, limiting their mobility, causing disability and pain, and seriously affecting their quality of life. Onset is observed in young adults in their 20's and 30's, with a pediatric form of MS becoming increasingly prevalent. While various current treatments delay progression or manage the symptoms, there is currently no cure and there is significant decline over a 15-20 year period with a large number of patients progressing from a relapsing remitting disease course to a progressive disease course.

For over 30 years, Einstein Pathology researcher Bridget Shafit-Zagardo, PhD, has worked to understand MS and give people suffering from the neurological disease hope.

“We’re predominantly interested in enhancing repair and functional recovery following central nervous system (CNS) injury,” said Dr. Shafit-Zagardo, a professor of pathology, who joined Einstein in 1984.



Enhancing repair



She explained that MS damages neurons, or nerve cells, and the myelin sheath - the insulation that surrounds and protects axons. The loss of myelin – demyelination - interferes with the transmission of normal nerve conductance required for nerves to signal between the brain, spinal cord and the rest of the body. 

“The goal is to repair axonal damage and enhance remyelination,” she said, noting that the current treatments address inflammation, but do not address nerve cell repair.

The exact antigen — or target that the immune cells are sensitized to attack — remains unknown, which is why MS is considered by many experts to be "immune-mediated," she said.

Abnormally hyper-activated infiltrating immune cells cross the blood brain barrier and induce inflammation in the CNS. As a result, resident cells of the CNS become activated and secrete inflammatory molecules that further enhance inflammation resulting in damage to neurons and oligodendrocytes, the myelin-synthesizing cells of the CNS. Axonal damage, destruction of myelin and activation of astrocytes called astrogliosis, ultimately result in CNS lesions referred to as glial scars or plaques in areas of damage. The resulting insult affects nerve fibers producing symptoms that may affect vision, coordination and mobility, and continence, among other symptoms.  

To that end, Dr. Shafit-Zagardo and her team are investigating strategies to slow the progression of axonal damage and demyelination and to enhance remyelination.

“Until damaged myelin and cell debris resulting from inflammation are cleared, you do not have efficient repair and recovery cannot occur,” said Dr. Shafit-Zagardo. The lab’s ongoing projects include applying techniques of molecular & cell biology, biochemistry, immunocytochemistry, confocal and electron microscopy to address questions concerning the structure, function and regulation of myelination in the normal CNS and remyelination following neuroimmune injury.



Identifying signaling pathways



Central to the treatment of MS is how cell signaling pathways regulate oligodendrocyte cell survival and remyelination after the inflammatory response.
Toward this goal, the lab has used molecular approaches to identify several genes implicated in signaling pathways that regulate oligodendrocytes and protect against demyelination. Among those genes identified were members of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases. As Dr. Shafit-Zagardo explained, to clear debris in MS lesions, the ligand or growth factor binds to receptors on the cell and signals downstream, recruiting signaling molecules that are protective for survival of the cell and also serve to activate other signaling pathways necessary for repair. The lab has demonstrated that signaling through the growth arrest-specific protein 6 (Gas6)/TAM pathway protects oligodendrocytes against injury.

Dr. Shafit-Zagardo’s research is funded by grants from the National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke. Assisting Dr. Shafit-Zagardo in her research is postdoctoral fellow Ross Gruber, graduate student Alex Ray and technician Kathleen O’Guin. Ross and Alex have been generating different mouse models, including single and double knockout mice that can be used to study different signaling pathways.



Moving forward



Despite her many achievements both inside and outside of science, the Bronx native has not had to venture far. After earning her master’s degree in biology at New York University, she studied human genetics with Dr. Robert Desnick and was awarded a PhD from City University of New York/ Mount Sinai School of Medicine, where her research focused on lysosomal storage diseases focusing on Gaucher’s disease. She initially joined Einstein as a postdoctoral research fellow under the mentorship of Dr. Joseph Maio in Cell Biology, working on long interspersed repetitive sequences. Dr. Shafit-Zagardo became involved in MS after seeing that early developmental genes could be turned back on during remyelination, and continued to expand on those initial studies.

MS research has come a long way in the last two decades. “Thirty years ago, there were no real treatments,” Dr. Shafit-Zagardo said, noting that the last 20 years has seen a variety of medications used for MS to block inflammation, but they do not target myelin repair.

Moving forward, her lab will continue to work toward developing better treatment and attempt to attempt to find factors that can aid in repair. She said, “Once we’ve determined how signaling occurs we will be able to use this information to protect against further damage."





Recent News 

ZhuHalmos-microscope Teaming Up to Bring Life-Saving Immunotherapy to Cancer Patients Montefiore’s IHC Laboratory and Clinical Oncology Team Up to Bring PD-L1 Testing for Cancer Immunotherapy In-House

Fooksman Visualizing the Immune Response Einstein Researchers Uncover Early Events in Severe Malaria Via Real-Time Video

 

MayaJoining Forces to Validate a Novel Biomarker for Breast Cancer Metastasis. In December 2016, Joseph Sparano, MD, associate chair of medical oncology at the Montefiore Einstein Center for Cancer Care, presented an invited paper at the 39th San Antonio Breast Cancer Symposium in San Antonio, TX. Dr. Sparano reported on a study he led to clinically validate MetaSite (MS), a novel biomarker for metastasis in breast cancer. Joining him were two of his coauthors, Joan Jones, MD, and Maja Oktay, MD,PhD—both members of the Montefiore/Einstein Department of Pathology and Einstein’s Department of Anatomy & Structural Biology.

 

COMMENTARIES IN THE NEWS

Michael Prystowsky Michael Prystowsky, MD, PhD, “The People Have Spoken,” Archives of Pathology, February 2017.read the full article 

 

 

Michael PrystowskyDr. Prystowsky is also featured “An Ocean Apart,” a Q & A with leading British and American leaders in the field, on the role of pathology and pathologists. The Pathologist, January 2017.read the full article  

 

James PullmanJames Pullman, MD, PhD, and Jonathan Nylk, PhD, “Finely Tuned Microscopy,” The Pathologist, December 2016. read the full article 


 

RECENT GRANTS

louis-weissLouis Weiss, MD, MPH, was awarded a $2.1 million, five-year grant by the National Institute of Allergy and Infectious Diseases (NIAID) to continue his efforts to understand how microsporidia—a type of single-celled parasite--infects host cells via a unique invading structure called the polar tube. read more 
 
DavidFooksmanDavid Fooksman, PhD, and Gregoire Lauvau, PhD, received a two-year $250,000 R21 grant from the NIAID to continue their groundbreaking use of in vivo video to shed light on the type 1 interferon pathway, an inflammatory signal that appears to play a pivotal role in severe malaria. (For details, see in Published Research and Cross-Campus Collaborations.)

 

FernandoFernando Macian-Juan, MD, PhD, has received a five-year, $2 million grant from the NIAID to study how chaperone-mediated autophagy (CMA) in T cells regulates the cells’ function. CMA is a degradation system that cells use to break down and recycle their proteins.read more  

 

RachelRachel Hazan, PhD, has received a one-year, $300,000 grant renewal from the Avon Foundation to continue leading a study on the role of cell cycle inhibitor P21 in triple-negative breast cancer, with a focus on metastatic disease. Her project collaborators are Susan Fineberg, MD, and Joseph Sparano, MD.

Research

Experimental pathology aims to define disease in terms of fundamental molecular and cellular processes. Research in our Department is focused on critical issues in multiple disease classes. Areas of focus include 

Research in each of these areas is highly interactive, and the Department strives for a collegial atmosphere in which collaborations can flourish. This effort is conducted through a variety of department-level activities, including regular meetings to discuss work in progress and a departmental retreat at which students, postdoctoral fellows, residents and faculty all have opportunity to present and discuss their research.

Research Funding Program

The Department of Pathology has established a research funding program to encourage residents and fellows to participate in clinical pilot research projects. Up to $2,000 will be awarded per research project, for projects of up to two years in duration.

Research Faculty

Amanda Beck, DVM 

Geoffrey Childs, PhD 

Joan W. Berman, PhD 

Mahalia Desruisseaux, MD, PhD 

Amy Fox, MD  

David Fooksman, PhD  

Rachel Hazan, PhD 

Lawrence Herbst, DVM, PhD 

Huan Huang, MD 

Sunhee C. Lee, MD  

Fernando Macian, MD, PhD 

Maja Oktay, MD, PhD 

Harry Ostrer, MD 

Thomas J. Ow, MD 

Michael B. Prystowsky, MD, PhD 

Moshe Sadofsky, MD, PhD 

Laura Santambrogio, MD, PhD 

Bridget Shafit-Zagardo, PhD 

Herbert Tanowitz, MD 

Louis Weiss, MD 

 
 

AWARDS, HONORS & APPOINTMENTS

FernandoFernando Macian-Juan, MD, PhD, has been granted tenure in the Department of Pathology. Dr. Macian-Juan is a Professor of Pathology. The Macian-Juan laboratory studies the mechanisms that regulate the induction of T cell tolerance and exhaustion; reversal of tumor-induced T cell tolerance as an immunotherapeutic approach; autophagy and T cell function; and aging in the T cell compartment.

 

 

lauraLaura Santambrogio, MD, PhD, has been awarded tenure in the Department of Pathology. Dr. Santambrogio is a Professor of Pathology, of Microbiology & Immunology and of Orthopaedic Surgery. The Santambrogio laboratory investigates antigen processing and MHC class II presentation pathways; pathogenesis of autoimmune response to self antigens; analysis of the lymph formation and lymphatic transport.

 

 

mahaliaMahalia S. Desruisseaux, MD, has been named an Associate Professor of Pathology at Einstein. She also holds the title of Associate Professor of Medicine (Infectious Diseases). Dr. Desruisseaux’s research focus is cerebral malaria: mechanisms of longterm cognitive dysfunction; regulation and activation of vasoactive mediators; and on modulators of blood-brain barrier impairment, and of neuronal and glial cell dysfunction.

Wendy Szymczak, PhD, has been appointed Associate Director of the Clinical Microbiology Laboratory at Montefiore. Dr. Szymczak formerly served as assistant to Laboratory Director Michael Levi, PhD. She also holds the title of Assistant Professor of Pathology at Einstein. Prior to joining Montefiore, Dr. Szymczak completed a post-doctoral research fellowship at Einstein in 2013. She earned her doctorate in molecular genetics, biochemistry & microbiology from the University of Cincinnati College of Medicine in 2010.

Emelia Cortez, Phlebotomy Laboratory manager, and her team, received a certificate of RESPECT in January for their outstanding efforts to ensure that patients in the Phlebotomy Unit at Montefiore’s Greene Medical Arts Pavilion received excellent care despite the challenges of a particularly stressful day. The honor, bestowed on the recommendation of grateful patients, recognizes service that “exemplifies the behaviors of the Montefiore Standards of Respect.”
 

RECENTLY PUBLISHED RESEARCH

 
Over the past year, research studies by Pathology Department faculty members have been published in prestigious, peer-reviewed scientific journals.

View a sampling of these articles here. 
 

TRAINEE SPOTLIGHT

  Gloria Ramos-Rivera, MD, chief resident of the Anatomic and Clinical Pathology Program at Montefiore, has been awarded the College of American Pathologists’s Ventana Fellowship. Funded by Ventana Medical Systems, the $5,000 grant will allow Dr. Ramos Rivera to participate in an advanced elective in translational diagnostics. She will travel to Tucson, AZ, in June, for the four-week training. Read more. 
 
 Decoding the Mysteries of a Lethal Parasite
Tatsuki Sugi, DVM, PhD, a postdoctoral researcher in the laboratory of Dr. Louis Weiss, is shedding light on the survival mechanism of Toxoplasma gondii. Read more. 
 
Exploring Low-Intensity Focused Ultrasound’s Potential as Cancer Immunotherapy
Karin Skalina, a predoctoral fellow in the laboratory of Dr. Chandan Guha, is investigating a new application of ultrasound as a non-invasive approach to cancer immunotherapy. Read more. 

Women’s March 2017: Montefiore Pathology Resident Stands Up for Social Justice
Elizabeth Richards, MD, describes her experience as a participant in the Women’s March in Washington, DC, and in a follow-up event in New York City. Read more. 

NEW FACES

We welcome Fabiane Matos dos Santos, PhD, a Visiting Scientist from the Federal University of Espirito Santo (FUES) in Brazil, and Sangeetha Thangaswamy, PhD,  from the Satara Univerity School of Chemical and Biotechnology in India.

Read about Drs. Matos dos Santos and Thangaswamy, and see the roster of our new Pathology residents here. 

 
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