High-density lipoprotein (HDL) is often referred to as "good" cholesterol because it transports fat molecules out of blood vessels, protecting against stroke and heart disease. Now, researchers at Weill Cornell Medical College have discovered that HDL in blood also carries a protein that powerfully regulates immune function. Together they play an important role in preventing inflammation in the body.

In the study, published June 8 in Nature, the investigators found that a lipid molecule called sphingosine 1-phosphate (S1P) that is bound to HDL suppresses the formation of T and B immune cells in the bone marrow. In doing so, HDL and S1P block these cells from launching an abnormal immune response that leads to damaging inflammation, a hallmark of many disorders including autoimmune diseases, cardiovascular disease and neuroinflammatory disease, such as multiple sclerosis.

"Our study shows that S1P that is bound to HDL helps prevent inflammation in many tissues," said senior investigator Dr. Timothy Hla, director of the Center for Vascular Biology and a professor of pathology and laboratory medicine at Weill Cornell. "When there is less S1P that is bound to HDL in blood, there are more B and T cells that can be activated to produce unwanted inflammation."

Dr. Hla has been studying S1P for more than two decades. He discovered that it is a key regulator of vascular function, and that about 65 percent of S1P in blood is bound to apolipoprotein M (ApoM), a member of the lipoprotein family, within the HDL particle. But until this study, the researchers did not know what specific function HDL-bound S1P served.

The team, including first author Dr. Victoria Blaho, an instructor in pathology and laboratory medicine, and researchers from the National Institutes of Health and Stanford University, studied mice that lacked HDL-bound S1P.

Dr. Timothy Hla. Photo credit: Carlos Rene Perez

Mice lacking HDL-bound S1P developed worse inflammation in a model of multiple sclerosis. The reason for this, the investigators found, is that HDL-bound S1P suppresses the formation of T and B immune cells in the bone marrow. While both immune cells help fight infection, an overabundance of these cells can also trigger unwanted inflammation.

The findings help explain why blood HDL levels are such an important measure of cardiovascular health, Dr. Hla said.

"Blood HDL levels are associated with heart and brain health — the higher the HDL in blood, the less risk one has for cardiovascular diseases, stroke, and dementia," Dr. Hla said. "The corollary is that the lower the HDL, the higher the risk of these diseases." Blood levels of ApoM and S1P have not been studied in these diseases.

The findings further suggest that molecules that mimic HDL-bound S1P could be useful in reducing damaging inflammation that has gone awry, Dr. Hla said. Such molecules are not known and will need to be developed in the future.

However, a related S1P1 receptor inhibitor called Gilenya, has already been approved for use in multiple sclerosis, a condition in which the immune system attacks nerve fibers due to unwanted inflammation, Dr. Hla said.

"The unique function of HDL-S1P could be further exploited for innovative therapeutic opportunities," he said.

For this research, Dr. Blaho received funding from the National Institutes of Health (F32 CA14211), the New York Stem Cell Foundation (C026878) and the Leon Levy Foundation (supported through the Feil Family Brain and Mind Research Institute). Dr. Hla received funding from the NIH (HL67330 and HL89934), as well as through Fondation Leducq.

Dr. Joseph Fins, the E. William Davis, Jr., MD Professor of Medical Ethics, professor of healthcare policy and research, professor of medicine and professor of medicine in psychiatry, was elected to the International Neuroethics Society’s Board of Directors in June. The society promotes the development and responsible application of neuroscience through interdisciplinary and international research, education, outreach and public engagement.

Dr. Timothy Hla, professor of pathology and laboratory medicine and professor of neuroscience in the Feil Family Brain and Mind Research Institute, was appointed to the Arteriosclerosis, Thrombosis, and Vascular Biology Editorial Board on June 6 for a two-year term. The journal, a publication of the American Heart Association, ranks in the top five journals in both the Peripheral Vascular Disease and Hematology categories and is published monthly for an audience of academic clinicians and researchers.

Dr. Luican Sulica, the Sean Parker Associate Professor in Otolaryngology and professor of otolaryngology, was elected a member of the American Laryngological Association Council in April. The association is a scholarly organization of clinicians and researchers who have made significant contributions to the care of patients with disorders of the larynx and upper aerodigestive tract. Members are encouraged to elevate the standards of the fundamental teaching of laryngology in medical schools and postgraduate medical education. Council members serve one-year terms and are charged with managing all business for the association.

Dr. Timothy Hla, professor of pathology and laboratory medicine and professor of neuroscience in the Feil Family Brain and Mind Research Institute, received an Outstanding Achievement Award from the Eicosanoid Research Foundation during its 14th annual conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases on May 8 in Budapest, Hungary. Dr. Hla was recognized for his research on the role of sphingosine 1-phosphate in development, physiology and disease.

Dr. Samuel Selesnick, professor of otolaryngology, professor of otolaryngology in neurological surgery and professor of otolaryngology in neurology, gave the James Parkin Lecture at the 20th annual Utah Otolaryngology Update hosted June 20 – 21 in Salt Lake City, Utah. The two-day event is designed to analyze the complications and complexities of head and neck cancer surgery, identify new techniques for treating and minimizing hearing loss, as well as discuss the diagnosis, management and treatment options for laryngeal disorders.

Dr. Susan Vannucci, research professor of neuroscience in pediatrics and research professor of neuroscience in the Feil Family Brain and Mind Research Institute, chaired the "New Insights into Mast Cell Biology in Pediatric Health and Disease" symposium, hosted by the Pediatric Academic Societies during its annual meeting on May 3 – May 6 in Vancouver.

Dr. Madelon L. Finkel, director of the Office of Global Health Education and professor of clinical public health, was an invited speaker at the annual NAFSA: Association of International Educators conference hosted May 26-31 in St. Louis, Mo. Dr. Finkel spoke on the importance of global partnerships. With nearly 10,000 members, NAFSA is the world's largest nonprofit association dedicated to international education.

Dr. Timothy Hla, director of the Center of Vascular Biology and professor of pathology and laboratory medicine, was selected to be the chairperson for the International Society on Thrombosis and Haemostasis' 18th International Vascular Biology meeting slated for April of 2014 in Kyoto, Japan. The society is the global community of dedicated scientists and physicians specializing in bleeding and clotting disorders. It is dedicated to transformative scientific discoveries and clinical practices, the development of young professionals and the education of physicians, scientists and allied health professionals wherever they may live.

Dr. Babak Navi, assistant professor of neurology and assistant professor of neuroscience, received a Weill Cornell CTSC Grant Writing Honors Scholar award in May. A select few CTSC grant recipients are chosen each year for this honors program, which matches the scholar to an external National Institutes of Health grant writer in order to produce a high quality NIH application.

Dr. Elliot Servais, a resident surgeon, received the Distinguished Housestaff Award from the New York Weill Cornell Medical Center Alumni Council Nov. 15.

Dr. Carl Blobel, professor of physiology in medicine and professor of physiology and biophysics, received a Bayer Hemophilia Awards Program grant for his research in hemophilia. These grants are provided annually to early career investigators, fellows in training and other hemophilia care professionals to support the next generation of hemophilia care and treatment options. Dr. Blobel received the Special Project Award at an international hemophilia meeting in July.

Drs. Anna Dickerman, Alexander Harris and Akshay Lohitsa, residents in the Department of Psychiatry, won third place in the Mind Games competition at the American Psychiatric Association's annual meeting May 21 in San Francisco, Calif. Mind Games is a national residency competition that is intended to be fun and educational and that challenges the residents on patient care and medical knowledge. This is the third consecutive year the NewYork-Presbyterian/Weill Cornell team qualified for this competition.

Dr. Diane Felsen, associate research professor of pharmacology in urology, was appointed to the American Journal of Physiology - Renal Physiology Editorial Board for a one year term, July 1, 2013-June 30, 2014. The journal publishes original manuscripts on a broad range of subjects relating to the kidney, urinary tract and their respective cells and vasculature, as well as to the control of body fluid volume and composition.

Dr. Antonio M. Gotto Jr., dean emeritus of Weill Cornell Medical College, co-chair of the Board of Overseers, the Lewis Thomas University Professor and university professor of medicine, gave a plenary address on "Hypolidemic Drugs: Looking from the Past to the Future," at the Drug Discovery and Therapy World Congress 2013, hosted in Boston, Mass., from June 3-6. The congress provides a platform for all pharmaceutical scientists, internists and primary care physicians to discuss important international breakthroughs in drug discovery and new therapeutics. The focus of this conference was on the interdisciplinary fields of drug discovery, drug therapy and translational medicine.

Dr. Timothy Hla, director of the Center of Vascular Biology and professor of pathology and laboratory medicine, was elected as president of New York Lipid and Vascular Biology Research Club for the 2013-2014 term.

Dr. Charles Inturrisi, professor of pharmacology, received the Distinguished Service Award from the American Pain Society during its annual meeting May 16 in New Orleans, La. The award recognizes outstanding and dedicated service to the society, a multidisciplinary community that brings together a diverse group of scientists, clinicians and other professionals to increase the knowledge of pain and transform public policy and clinical practice to reduce pain-related suffering. Dr. Inturrisi is a past president of and former member of the board of directors for the society.

Dr. Bryan J. Schneider, the Madeline and Stephen Anbinder Clinical Scholar in Hematology/Oncology and assistant professor of medicine, was appointed as a member of the American Society of Clinical Oncology's Clinical Practice Guidelines Committee, which drafts clinical practice guidelines for cancer treatment and research. Dr. Schneider began his membership June 5 following the society's annual meeting in Chicago, Ill. The society is a professional oncology society committed to conquering cancer through research, education, prevention and delivery of high-quality patient care.

Dr. Thomas J. Walsh, director of the Transplantation-Oncology Infectious Diseases Program, professor of medicine, professor of medicine in microbiology and immunology and professor of medicine in pediatrics, was awarded the Exemplary Responder Award at the New York City Medical Reserve Corps Symposium June 2 for his service at the medical evaluation site during and after Superstorm Sandy. Dr. Walsh, who had been deployed to many disaster areas over the years, worked 12-hour shifts at the Park Avenue Armory shelter during last year's storm.

Weill Cornell Researcher Joins Forces with Fellow Scientists To Manage Risks Associated with Common Pain Killers

Dr. Timothy Hla, director of the Center for Vascular Biology and professor of pathology and laboratory medicine, is a key member of an interdisciplinary and inter-institutional research team from the Personalized NSAID Therapeutics Consortium.

Established by an $18.5 million grant from the National Institutes of Health's National Heart, Lung and Blood Institute, the consortium is comprised of an international group of scientists who are collaborating to develop a way to manage the risks of serious side effects due to differing responses to nonsterodial anti-inflammatory drugs, or NSAIDS. These drugs are used to relieve pain and inflammation — ibuprofen, naproxen and celebrex, for example — and are among the most common medications consumed worldwide, but physicians still do not know the best NSAID of choice for patients with arthritis and heart disease or if NSAIDs differ in clinical efficacy and risk for different individuals.

The consortium aims to use the power of contemporary "omics" technologies — genomics, proteomics, metabolomics — to address individual response to NSAIDs. Using NSAIDs that differ in their preferences for blocking the COX-2 enzymes, the molecules responsible for inflammation and pain, the researchers will seek to identify the molecular signatures that discriminate drug action in cells and model systems. Collaborators will then integrate this information with clinical trial data to understand how NSAIDs perturb biological networks, looking for both benefit and risk.

Researchers will be integrating data from studies involving yeast, mammalian cells, zebrafish, mice and humans for this larger study. Dr. Hla will receive $709,800 over the course of five years to test in mouse models the role of COX-2 regulatory factors, such as the RNA binding protein HuR, in vascular function and the effects of pain killers (NSAIDs and COXibs).

Public Health Researchers Receive Grants on Drug Addiction, Infectious Disease, Postoperative Infection

Two public health researchers were awarded a total of $1.8 million to conduct four research projects on drug abuse, infectious disease and postoperative infection.

Dr. Bruce Schackman, chief of the Division of Health Policy and associate professor of public health

Dr. Bruce Schackman, chief of the Division of Health Policy and associate professor of public health, was awarded a three-year R01 grant for $1,474,844 from the National Institute on Drug Abuse titled "Quality of Life Outcomes in Prescription and Injection Opioid Dependence."

The purpose of the study is to measure quality of life in opioid dependence using primary data from a survey of the US population and secondary data from opioid dependent patients enrolled in three national studies. Results will provide quality of life estimates and guidance for cost-effectiveness and comparative effectiveness studies of opioid dependence treatment. The study will also evaluate novel methodologies for assessing these outcomes.

Co-investigators include Dr. Jeremy Bray from RTI International, Dr. Yih-Ing Hser from University of California Los Angeles, Dr. Bohdan Nosyk from the British Columbia Centre for Excellence in HIV/AIDS and Dr. Eve Wittenberg from the Harvard School of Public Health. Study staff includes Jared Leff, program supervisor in the Division of Health Policy, and Allison Dunning, research biostatistician in the Division of Biostatistics and Epidemiology, both at Weill Cornell.

Dr. Nathaniel Hupert, associate professor of public health and associate professor of medicine

Dr. Schackman also received a new sub-award for a five-year grant from the National Institute on Drug Abuse titled "Intensive Models of HCV Care for Injection Drug Users." The dollar amount awarded for the first year of the subcontract is $75,234. In this study, patients from methadone clinics will be randomized to one of three models of hepatitis C care: directly observed therapy; concurrent group treatment; or standard on-site care. The principal investigator is Dr. Alain Litwin of Albert Einstein College of Medicine and Jared Leff is a staff member on the grant. Dr. Schackman and Leff will oversee cost data collection and analyze the costs of delivering care in the study, and Dr. Schackman will contribute to the cost-effectiveness analysis design and implementation.

Dr. Schackman is but one public health researcher to be awarded grants this summer. Dr. Nathaniel Hupert, associate professor of public health and associate professor of medicine, has also been awarded a renewed contract with the Centers for Disease Control and Prevention for preparedness modeling. In the one-year $194,840 grant, which ends next June, Dr. Hupert will lead a number of computational modeling activities at the CDC's National Center for Emerging and Zoonotic Infectious Diseases. These will include projects on detection and response to special pathogens such as Bacillus anthracis; resource modeling for public health and medical response to a variety of emergency scenarios; and improved "public health information engineering" for improved logistical capability after detection of disease outbreaks.

Additionally, Dr. Hupert has also been awarded a contract with Hospital for Special Surgery for $80,000 to create a computer model to explore strategies for reducing the rate of postoperative infection for spinal surgery. This project will employ quantitative and qualitative methods to better understand the potential causes of hospital-acquired infection for patients undergoing spinal surgery at Hospital for Special Surgery. The goal of the project is to identify promising targets for infection-reduction interventions in the process of care for patients undergoing spinal surgeries.

Additional Grants

Dr. Heather H. McCrea, a fourth-year neurosurgery resident, is among 10 researchers awarded $40,000 grants for 2012-2013 by the Neurosurgery Research and Education Foundation. Dr. McCrea's study is titled "The Role of Angiocrine Expression of Notch Ligands in Glioma Progression." She is sponsored by Dr. Shahin Rafii. The Foundation provides research funding opportunities as a means to make advances in the diagnosis and treatment of neurological conditions such as brain tumors, strokes and spinal disorders. Applications for the grant were reviewed by the Foundation's Scientific Advisory Committee. Once submissions were evaluated, the SAC provided funding recommendations to the Foundation's Executive Council.

Dr. Siobhan Pattwell, a postdoctoral fellow in the Sackler Institute for Developmental Pyschobioloy, and Dr. Deqiang Jing, assistant professor of neurobiology in psychiatry, were two of more than 200 researchers to receive National Alliance for Research on Schizophrenia and Depression Young Investigator Grants from the Brain and Behavior Research Foundation. Dr. Pattwell will receive $60,000 over the course of two years to identify windows of maximal opportunity for therapeutic interventions that are tailored to appropriate individuals at the most appropriate time. She hopes to do this by delineating age-specific variation in the regulation of fear responses that are at the very core of therapeutics for anxiety disorders. She will perform parallel mouse and human studies to investigate the developmental role of reconsolidation update on the erasure of conditioned cued and contextual memories. Similarly, Dr. Jing will also receive $60,000 over the course of two years to test the hypothesis that deficiency of a gene called Slitrk5 leads to OCD-like behaviors as a result of altered formation of the synapse, the site where brain-cell communication takes place. Dr. Jing will include detailed analyses of the role Slitrk5 in synapse formation in vitro and in further animal studies. The Brain and Behavior Research Foundation is dedicated to identifying the causes, improving treatments and developing prevention strategies for mental illnesses.