Research | Mount Sinai Today

Educating Providers on the Impact of Climate Change

Mar 5, 2019 | Featured, Research

From left: Robert O. Wright, MD, MPH; Emily Senay, MD, MPH; Allan Just, PhD, Assistant Professor of Environmental Medicine and Public Health; Perry E. Sheffield, MD, MPH, Assistant Professor of Environmental Medicine and Public Health; and Roberto Lucchini, MD.

Climate change is taking a toll not just on the environment, but also in the clinic, with a rise in asthma, cardiovascular disease, insect-borne viruses, and heat-related death. That was the urgent message of the inaugural Clinical Climate Change conference, hosted by Mount Sinai’s Institute for Exposomic Research. Panelists at the event, held on Saturday, January 12, at the New York Academy of Medicine, included environmental advocates and leaders in the study of environmental medicine and public health.

The conference aimed to provide public health professionals, policymakers, physicians, nurses, medical students, and allied health professionals with a base of up-to-date evidence to inform patient treatment and care as the global average temperature continues its steady rise. “Air pollution is a major driver of the health consequences of climate change,” said Robert O. Wright, MD, MPH, Professor and Ethel H. Wise Chair of the Department of Environmental Medicine and Public Health, and Director of the Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai. “In addition to conditions you would expect to increase, such as asthma and other lung diseases, our research shows that there are many downstream effects.” For example, Dr. Wright and several other panelists focused on fine particulate matter (PM2.5) from air pollution, which causes inflammation in the body that is associated with neurotoxicity, neurodevelopmental disorders, and increased insulin resistance.

Heat-related conditions are of particular concern for outdoor workers. Thousands become sick every year, and many die, due to these preventable illnesses, said Roberto Lucchini, MD, Professor of Environmental Medicine and Public Health, Icahn School of Medicine. “Studies show that recurrent heat exposure, with physical exertion, inadequate hydration, and exposure to chemicals, can lead to chronic kidney disease,” he said. “There is an epidemic of this disease among worker populations in Central America. We have to prepare health care workers in northern areas to be aware of the condition.”

In addition to these critical warnings, speakers presented actionable tools for clinicians both to better inform patients and to modify their practice. “Physicians can explain the importance of paying attention to heat and poor air-quality days,” said Emily Senay, MD, MPH, Assistant Professor of Environmental Medicine and Public Health, Icahn School of Medicine. “This is especially important for vulnerable patients who are elderly or chronically ill.” During a heat wave, clinicians might consider adjusting some medications, like diuretics, which reduce the ability to lose heat by sweating. And they should advise patients to close windows and use air conditioning to limit exposure to air pollution but also to be conscious of indoor pollutants like mold and fumes from cleaning products.

Physicians were encouraged to prepare for an influx of diseases previously unseen in their population, particularly those carried by insects. A warming climate will make habitats more hospitable to disease-carrying insects, such as mosquitoes and ticks, exposing a larger swath of the population to diseases such as Lyme disease, Zika virus, and dengue fever.

Another concern is that weather events, such as hurricanes and floods, are becoming more extreme as a result of climate change. Superstorms of recent years, like Hurricane Sandy, are leading to a shift from an “emergency response” model to a more forward-looking “risk mitigation” approach, said George Loo, DrPH, MPH, Assistant Professor of Emergency Medicine, and Population Health Science and Policy, Icahn School of Medicine. That includes moving critical infrastructure out of flood prone areas and developing extensive logistics for managing transportation, power, security, and staffing. In addition, Dr. Loo said, “Health care workers need to first have a plan to take care of themselves and their families. Knowing that your family is safe and that you have a way to contact them will reduce stress and help you focus on your patients.”

Physicians play an important role in helping patients understand how climate affects the health of individuals and how, at a population level, humans affect the environment, Dr. Senay said. With a nuanced approach, she added, providers can improve environmental literacy and open the door to discussions about how walking more, eating a plant-based diet, and advocating for renewable energy can make both the planet and patients healthier.

Department of Neuroscience at the Icahn School of Medicine at Mount Sinai Ranked No. 1 in Nation in NIH Funding

Updated on Jun 30, 2022 | Featured, Research

The Nash Family Department of Neuroscience at the Icahn School of Medicine at Mount Sinai received the most biomedical research funding from the National Institutes of Health (NIH) of any medical school neuroscience department in the nation in 2018, according to data compiled and released by the Blue Ridge Institute for Medical Research.

Paul J. Kenny, PhD

Seven other academic and clinical departments at the Icahn School of Medicine ranked among the top 10 nationally. They were Microbiology (No. 3), Emergency Medicine (No. 4), Pharmacology (No. 4), Genetics (No. 5), Anatomy/Cell Biology (No. 6), Psychiatry (No. 6), and Neurology (No. 10). Altogether, these seven disciplines and Neuroscience at Mount Sinai were awarded $184 million from the NIH in 2018.

The Neuroscience Department’s No. 1 ranking reflects $31.2 million in awards received during the NIH’s 2018 fiscal year and includes 41 awards for which department faculty members are Principal Investigators.

“We are thrilled by this outstanding achievement, which is a milestone for the neuroscience community at Mount Sinai. This is a testament to the outstanding quality of our faculty, postdoctoral fellows, graduate students, and staff, and reflects the cutting-edge research conducted in our laboratories,” says Paul J. Kenny, PhD, Chair of the Department. “These highly competitive funds enable Mount Sinai researchers to pursue initiatives that advance understanding of human health and disease and to swiftly develop treatments and technologies that will change the lives of patients worldwide.”

Eric J. Nestler, MD, PhD

Each year, Blue Ridge releases its analysis of NIH funding, ranking individual departments by total award dollars.

“Through a large, multidisciplinary effort that involves numerous basic science and clinical departments, we have made impressive strides in understanding how the nervous system functions under normal conditions and malfunctions in disease, making us uniquely poised to translate these advances into fundamentally new and improved treatments for some of the world’s most devastating disorders,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic and Scientific Affairs at the Icahn School of Medicine at Mount Sinai.

Consortium Sheds New Light on Brain Disorders

Updated on Jun 30, 2022 | Featured, Neuroscience, Psychiatry, Research

From left: Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry; Prashanth Rajarajan, MD/PhD candidate; and Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience.

Reprinted with permission from AAAS.

More than two dozen researchers at the Icahn School of Medicine at Mount Sinai are advancing brain science by mapping the complex molecular underpinnings of autism spectrum disorder, schizophrenia, and bipolar disorder through their work in the National Institute of Mental Health’s (NIMH) PsychENCODE Consortium. Since this work began in 2015, their contributions—and that of their PsychENCODE colleagues from 14 other U.S. institutions—have helped identify several hundred new risk genes for mental disorders. The research has also revealed critical time windows during brain development when these genes can influence the disease process.

In December, the Consortium published its initial findings in 10 studies that appeared in Science, Science Translational Medicine, and Science Advances. The researchers analyzed more than 2,000 postmortem brain samples from people with no psychiatric conditions and those with schizophrenia, autism, and bipolar disorder. They created and then integrated data sets that included information on DNA variations and gene expression for about 32,000 cells from major regions of the brain. Then the investigators employed machine learning to create a predictive model of risk for the psychiatric disorders.

Their seminal findings received an enthusiastic response from the NIMH. “The PsychENCODE project came through,” said Thomas Lehner, PhD, MPH, Director of the Office of Genomic Research Coordination at the NIMH. “We’re at the beginning—I cannot overstate how early we are. But I can confidently say that for the first time we have a beginning of an understanding of the biology—the molecular pathophysiology of mental disorders—of schizophrenia, and bipolar and autism spectrum disorder.”

Unraveling the Complexity of the Human Brain

“Exploring how the human genome is folded and packaged into the nucleus of each of our billions of brain cells was both awe-inspiring and humbling at the same time,” says Prashanth Rajarajan, MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, who was first author on seminal brain research that was published in the December 14, 2018, issue of Science.

The scientific team discovered that early development is associated with major changes in the spatial organization of DNA inside of brain cells. These changes in how the chromosomal material is packed seem to disproportionately affect DNA sequences linked to schizophrenia heritability risk and provide new insights into the genetic causes underlying this disease.

The study, which was conceived and executed at the Icahn School of Medicine, included senior authors Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience; and Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry. Colleagues at the New York Genome Center and the University of Massachusetts also contributed to the study.

According to Mr. Rajarajan, “There is so much more to the genome than just the four-letter DNA code (A, T, C, G)—such as its folded architecture, which is a highly organized and regulated process. Eighteen years after fully sequencing the human genome, we still understand very little about how it actually comes to life. Our study, and the others that were published, are beginning to unravel more nuances than previously imagined, making it a really exciting time to be in the field of neuroscience and psychiatry research.”

NIMH Program Director Geetha Senthil, PhD, added that the massive scope of the project required a “concerted effort. Many investigators had to come together and do this collectively.” While the mental disorders in the studies are distinct, Dr. Senthil said, “There are some aspects where the biology is similar. The genes interact with each other in a way to influence the disease process. If we can find biological clues early on, we can intervene early on. While we are building and generating more data, analyzing this data to find basic mechanisms, there’s an opportunity also for drug discovery.”

The 10 papers published by the PsychENCODE Consortium were dedicated to the late Pamela Sklar, MD, PhD, former Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine, and a pioneer in genomic brain research, who was an early leader of the NIMH effort. The Icahn School of Medicine last year renamed the division she created the Pamela Sklar Division of Psychiatric Genomics.

Mount Sinai laboratories within The Friedman Brain Institute, The Seaver Autism Center for Research and Treatment, the Department of Psychiatry, The Mindich Child Health and Development Institute, the Department of Genetics and Genomic Sciences, the Department of Neuroscience, and the Icahn Institute for Data Science and Genomic Technology were involved in the PsychENCODE Consortium.

“Mount Sinai serves as one of the lead sites in this national consortium. The discoveries that are being made by our scientists and their colleagues at other major institutions are moving us closer to understanding and finding treatments for these devastating brain disorders,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic and Scientific Affairs, Icahn School of Medicine at Mount Sinai.

Mount Sinai and Sema4 Launch Groundbreaking Asthma Study With Global Pharmaceutical Company

Updated on Jun 30, 2022 | Featured, Patient Stories, Research

Andrew Kasarskis, PhD, left, and Linda Rogers, MD, are part of the asthma study team.

Asthma, a chronic disease of the airways of the lungs, is a growing public health problem that now affects 350 million people and results in about 400,000 deaths worldwide each year. Its diagnosis and treatment remain challenging, however, and debilitating symptoms, such as coughing and shortness of breath, are a major cause behind rising health care costs, missed school for children, and loss of productivity and early disability in adults.

Recently, the Mount Sinai Health System and Sema4—a patient-centered predictive health company and a venture of Mount Sinai—joined with Sanofi, one of the world’s largest pharmaceutical companies, to follow 1,200 Mount Sinai patients to gain unprecedented insights into the biological mechanisms and environmental factors implicated in this condition.

The five-year study—the first of its kind—will collect traditional clinical data, such as electronic medical records and clinical samples, including blood samples and nasal brushings, from patients during their doctor appointments. The data will be analyzed for genomic and transcriptomic information and combined with other data collected using the patient’s mobile phone—environmental data, like air quality and pollen counts, data from the patient’s asthma inhaler, and data from home monitoring of activity and sleep. One of the unique elements of this study is that the research will be incorporated into actual clinical practice, and real-world data using remote devices will be integrated with molecular data.

“Despite advances in recent years, we still see many patients struggling with asthma, so there is a tremendous need for innovation to reduce the burden of this disease,” says Linda Rogers, MD, Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) and Clinical Director of the Adult Asthma Program at the Mount Sinai – National Jewish Health Respiratory Institute. Dr. Rogers is the clinical principal investigator of the study, which is a collaboration among the Respiratory Institute, the Icahn Institute of Genomics and Multiscale Biology, Sema4, and Sanofi.

The Respiratory Institute is uniquely positioned to undertake this research. In addition to the large number of asthma patients that the program treats, the Mount Sinai and Sema4 study team have unparalleled capabilities in specimen analysis, data science, and multiscale biological modeling, allowing researchers to gather large amounts of data more rapidly than using more traditional research methods.

Clinical research teams will deploy advanced analytics on this information to better understand how the disease functions, including what triggers asthma attacks and which patient segments are most likely to respond to certain therapies. “This collection of large amounts of multiple types of data is needed to fully understand asthma—a condition researchers now believe is far more complex than was previously understood—and how best to treat patients,” says Tom Neyarapally, Sema4’s Chief Commercial Officer.

Significantly, gathering and analyzing these kinds of data from patients will demonstrate at the molecular level how their bodies are responding to asthma, says Andrew Kasarskis, PhD, Executive Vice President and Chief Data Officer for the Mount Sinai Health System and a co-principal investigator of the study. For example, analysis of a blood sample will show changes in the cellular activity, such as which proteins are being produced, and a nasal swab may reveal important clues about one’s immune response and what is happening in the lungs.

“We will define asthma subtypes clinically, then understand the molecular basis of disease in each subtype in order to discover new therapies and better manage asthma in all our patients,” says Dr. Kasarskis.

Ultimately, adds Erik Lium, PhD, Executive Vice President of Mount Sinai Innovation Partners, “this collaboration may lead to the identification of novel drug targets and the development of groundbreaking therapies to benefit all patients with asthma.”

New Pathway to Treating Rheumatoid Arthritis Identified

Updated on Jun 30, 2022 | Featured, Research, Your Health

Pércio S. Gulko, MD, center, with team members Teresina Laragione, PhD, Assistant Professor of Medicine (Rheumatology), left, and Carolyn Harris, Senior Associate Researcher.

A new gene associated with disease severity in rheumatoid arthritis (RA) has been identified by researchers at the Icahn School of Medicine at Mount Sinai. This finding could provide a new pathway for treatment and a way to measure the prognosis of patients diagnosed with this autoimmune condition.

Through a series of experiments, Pércio S. Gulko, MD, Chief of the Division of Rheumatology, and the Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and his colleagues showed that Huntingtin-interacting protein 1 (HIP1) is a driver in inflammatory arthritis severity. The findings were published in July 2018 in the Annals of the Rheumatic Diseases. “It is known that this gene is expressed in some cancers, but precisely how it contributed to cancer was not known, and it has never been implicated in inflammation or arthritis. So this new discovery, that it regulates cell invasion, is completely novel,” says Dr. Gulko, senior author of the paper.

Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease causes pain, swelling, and sometimes deformation of joints and affects about 1 percent of the world’s population. In the last 20 years, there have been major advances in the treatment of RA, but the existing treatments immunosuppress patients, increasing the risk for infections.

Dr. Gulko with images of synovial fibroblasts, cells in the joints that are central to his team’s study of rheumatoid arthritis.

“At my laboratory, we have been looking for alternative strategies,” Dr. Gulko says. “We have focused on understanding the regulation of disease severity and joint damage, and this led us to the synovial tissue and the fibroblasts.” These cells are present in all joints and produce the fluid that lubricates and nourishes the cartilage, but in patients with RA, they grow out of control, invading and destroying cartilage and bone.

Dr. Gulko’s team started with rodent models of arthritis, studying animals that were highly susceptible to RA and those that were resistant. Using a technique called positional cloning, the researchers identified gene variants that control arthritis severity and the behavior of the synovial fibroblasts, finding that HIP1 made the cells highly invasive. Next, the team studied synovial fibroblasts from patients with RA and found that HIP1 was strongly expressed in those cells. To test the finding further, the team used a molecular biology technique to “knock down,” or remove, HIP1 from the cells of RA patients, and found that this significantly reduced the cells’ ability to invade.

The team unexpectedly found further evidence implicating HIP1 while collaborating in a study of RA and epigenetics, the environmental influence on genetics. The study, which was published in May 2018 in Nature Communications, compared the synovial fibroblasts of patients with RA with those from patients with osteoarthritis, which is not considered an inflammatory disease. The researchers were looking for dysregulated genes and pathways that differentiated the two groups of patients.

“One key pathway found to be epigenomically dysregulated was the Huntington protein pathway, including HIP1,” Dr. Gulko says.

Going forward, Dr. Gulko has several goals: improving the understanding of how HIP1 regulates disease; finding a way to quantify HIP1 levels in the blood or synovial fluid cells with the aim of creating a predictor of disease prognosis; and developing a drug that would target the HIP1 gene. The ultimate goal is to achieve remission for RA patients.

“I treat many patients with rheumatoid arthritis,” Dr. Gulko says, “and all the work that we have done throughout my career has been centered on trying to bring a benefit to these patients.”

FAMILIA Trial Teaches Healthy Habits at Early Age

Updated on Jun 30, 2022 | Community, Featured, Research

Natalia Leal and her son Gabriel are participants in FAMILIA, which instructs preschoolers and their families on cardiovascular health.

Children will listen. That is the simple premise underlying FAMILIA, a trial developed by Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, to promote cardiovascular health among children while reducing their chances of developing risk factors for heart disease.

The “Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health” (FAMILIA) trial enrolled 600 families in Harlem, including 562 children ages 3 to 5, over the last four years. It has demonstrated that a school-based education intervention is an effective strategy for instilling healthy behaviors among preschoolers, according to an abstract that Dr. Fuster presented in November 2018 at the American Heart Association Scientific Sessions in Chicago.

Dr. Fuster is a pioneer in the study of atherosclerotic disease—the build-up of fats, cholesterol, and other substances in and on artery walls—which is the leading cause of death in the United States. It develops slowly over a lifetime and is often caused by such factors as an unhealthy diet, lack of exercise, and tobacco use.

“There is good data showing that part of our behavior as adults develops between ages 3 and 5,” Dr. Fuster says. “If this age is so important, why wouldn’t we use this window of opportunity to teach children to make health a priority for the rest of their lives?”

Funded by a $3.8 million grant from the American Heart Association, FAMILIA is based on successful health interventions that Dr. Fuster developed in Bogota, Colombia, and Spain. Like those programs, FAMILIA is exploring how a child’s behavior, environment, and genetics may lead to heart disease, with the goal of reducing the future risk of obesity, heart attack, stroke, and type 2 diabetes by creating a family-based “culture of health.”

The specific objective of the FAMILIA trial was to “assess the impact of a preschool-based health promotion education intervention in an underserved community.” It enrolled children in 15 Head Start preschools, forming a cohort that was 51 percent female, 54 percent Hispanic/Latino, and 37 percent African American. Children were randomly assigned to either a control group that received their school’s normal curriculum or a group that received 50 hours of heart-health education over four months.

At the start, each child was interviewed by a team member with experience in early childhood education, using tools that were pictorial and structured like an interactive game. Based on the results, each child was given a KAH (knowledge, attitudes, and habits) score. The children who received intervention learned lessons, including: how the heart works; how to select healthy foods; how to regulate their emotions; and how to stay physically active and encourage their families to be active, too. After four months, researchers interviewed the preschoolers again and measured the change in KAH from the baseline.

Researchers found that the overall KAH score rose 11.8 percent from the baseline in the intervention group, compared with 5.5 percent in the control group. Based on the children’s responses, their attitudes about staying active and their understanding of the human body and heart were the biggest drivers of the higher KAH scores, researchers said. The team is planning to conduct a long-term follow-up at five and ten years to assess the sustainability of the intervention effects.

FAMILIA also includes a parallel program for the parents and caregivers of children in the trial. Some adults meet in small groups to help each other get healthier through peer support, while others receive individualized lifestyle counseling and a personal activity-monitoring device. Results from that program are expected in late 2019.

“What we are finding is a significant benefit in all respects,” Dr. Fuster says of both adults and children in FAMILIA. “Their knowledge, their attitudes, and their habits are quite positive, and this is very exciting.”

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