Post-Doc in the Kolesnick Lab | Anti-Ceramide Strategies to Improve Wound Repair

The people of Memorial Sloan Kettering Cancer Center (MSK) are united by a singular mission: ending cancer for life. Our specialized care teams provide personalized, compassionate, expert care to patients of all ages. Informed by basic research done at our Sloan Kettering Institute, scientists across MSK collaborate to conduct innovative translational and clinical research that is driving a revolution in our understanding of cancer as a disease and improving the ability to prevent, diagnose, and treat it. MSK is dedicated to training the next generation of scientists and clinicians, who go on to pursue our mission at MSK and around the globe. One of the world's most respected comprehensive centers devoted exclusively to cancer, we have been recognized as one of the top two cancer hospitals in the country by U.S. News & World Report for more than 30 years.

Endothelial cells contain 20-fold more acid sphingomyelinase (ASMase) than any other cell in the body. ASMase hydrolyzes sphingomyelin, which is preferentially concentrated in the outer leaflet of the plasma membrane of all mammalian cells, to generate the second messenger ceramide. We initially showed that high dose ionizing radiation activates endothelial cell ASMase, thereby inducing apoptosis and microvascular dysfunction in multiple murine organs, and that ASMase KO mice are resistant to all clinically-relevant radiation doses (Santana et al., Cell 1996, 86:189-199). Our lab was studying normal tissue damage prior to 9/11 and showed that ASMase/ceramide mediated vascular damage played a fundamental role in lethality from the Gastrointestinal-Acute Radiation Syndrome (GI-ARS) in mice (Paris et al., Science 2001, 293:293-7), one of two potentially lethal syndromes that might occur after a nuclear catastrophe. Based on this observation, we generated anti-ceramide antibodies (Abs) to bind ceramide formed on the endothelial cell surface, which we showed protect and mitigate radiation-induced endothelial cell apoptosis (Rotolo et al., J Clin Invest 2012, 122:1786-90). In collaboration with the Radiation Countermeasures Program at the NIH, the Department of Defense, and a company co-founded by our program entitled Ceramedix Inc., we have been developing an anti-ceramide Ab to attempt to protect/mitigate GI-ARS lethality. Recently, we showed that anti-ceramide Ab delivery at 24 hours post irradiation of C57BL/6J mice to prevent ongoing apoptotic death in vasculogenic endothelial progenitors entering the damaged small intestines, facilitates microvascular reconstitution, yielding immediate regeneration of the critical Lgr5+ small intestinal stem cell compartment (Rotolo et al., JCI Insight 2021, 6:e145380). This finding, linking ongoing endothelial apoptosis to stem cell fate, if corroborated in other organs, may change our view of tissue damage repair. A pilot monkey trial at the NIH showed that our anti-ceramide strategy is highly effective in treating endothelial cell apoptosis in rhesus macaques exposed to a GI-ARS lethal radiation dose, supporting human translation of this technology.

In collaboration with Julia Busik, an expert in diabetic retinopathy (DR) at the University of Oklahoma, we extended our interest in anti-ceramide inhibition of endothelial cell apoptosis to DR, a vasculopathy which is a leading cause of blindness worldwide. We have definitive proof, using all conventional models of DR in mice/rats, that the vascular dysfunction associated with diabetes is abrogated in ASMase knockout mice or by anti-ceramide Abs injected directly into the eye of diabetic wild type mice [Dorweiler et al., Cell Metabolism 2024 (in press)]. This finding has generated enormous enthusiasm in the DR community as the current clinical strategy, to inject anti-VEGF into the vitreous, only prevents the disease from progressing, whereas anti-ceramide has the potential to prevent the cause of the disease, endothelial cell apoptosis. Ceramedix Inc. is currently in the process of developing anti-ceramide Abs for treatment of DR.

The available project represents an extension of the collaborative work with Julia Busik on proliferative DR. It is supported by significant pre-clinical data that show anti-ceramide strategies, when delivered systemically or topically, enhance diabetic and normal repair of full thickness skin wounds. Focus will be on the role of microvascular progenitors in the preservation/regeneration of the reparative Lgr5+ stem cell in the hair follicle. This project is more than half complete and needs full time attention in order to prepare the project for submission to a high impact journal. This project will rely heavily on next generation sequencing (single cell and spatial scale), organoid technology, CRISPR interrogation, multiplexed flow cytometry and tissue confocal microscopy. It is anticipated that if we can show that anti-ceramide protection of the reparative microvasculature results in enhanced stem cell survival and improved wound repair, we will pivot to development of this anti-ceramide strategy to improve stem cell transplantation in a variety of clinically-relevant settings.

Salary: $61, 150- $75,000

Interested candidates please send curriculum vitae brief statement of prior research experience and research interests, and contact information for three references in your application submission to:

Richard Kolesnick
Professor of Molecular Pharmacology
Weill Cornell Medical College
Member, Sloan Kettering Institute
e-mail: r-kolesnick@ski.mskcc.org

If you have any questions about this job opprtunity, please contact:

Christina Provenzano provenc@mskcc.org

#LIOnsite

MSK is an equal opportunity and affirmative action employer committed to diversity and inclusion in all aspects of recruiting and employment. All qualified individuals are encouraged to apply and will receive consideration without regard to race, color, gender, gender identity or expression, sexual orientation, national origin, age, religion, creed, disability, veteran status or any other factor which cannot lawfully be used as a basis for an employment decision.

Federal law requires employers to provide reasonable accommodation to qualified individuals with disabilities. Please tell us if you require a reasonable accommodation to apply for a job or to perform your job. Examples of reasonable accommodation include making a change to the application process or work procedures, providing documents in an alternate format, using a sign language interpreter, or using specialized equipment.