September 3, 2015—(BRONX, NY)—The Research Project Grant (R01) supports health-related research and development and historically was the first type of grant awarded by the National Institutes of Health (NIH). Three Einstein researchers recently received their first R01 grants—a major milestone in an academic scientist’s career. Below we describe their R01-funded research, followed by research descriptions of several other Einstein faculty members who received new R01s between October 1, 2014 and June 31, 2015.

Michal L. Melamed, M.D.Dietary Supplements Against Kidney Disease. Some 66 million Americans have hypertension, putting them at risk for kidney disease. Animal studies and observational studies in humans suggest that vitamin D and omega-3 fatty acids may protect against kidney disease. The NIH has awarded Michal Melamed, M.D., $3.5 million over five years to take part in its ongoing VITamin D and OmegA-3 TriaL (VITAL). In this multistate clinical trial, more than 25,000 men over 50 and women over 55 are taking either vitamin D3, omega-3 fatty acids or placebo to evaluate the supplements’ effects on cardiovascular disease and cancer. To date, the five-year VITAL has not assessed kidney function. For a subgroup of 4,000 VITAL participants who had hypertension at the start of the trial, Dr. Melamed is evaluating their kidney function after their fourth year of participating in VITAL, to see if either supplement helps prevent kidney disease. Dr. Melamed is associate professor of medicine and of epidemiology & population health at Einstein and attending physician, nephrology, Montefiore Health System.

Julie Secombe, Ph.D.Studying Proteins that Trigger Cancer. Cells control gene activity by regulating transcription, the process that converts DNA into messenger RNA, which acts as a template for constructing proteins. Transcription factors are proteins that interact with DNA to initiate, speed up or slow down gene transcription. Other proteins, called transcriptional regulators, orchestrate the activity of transcription factors. The NIH has awarded Julie Secombe, Ph.D.,a five-year, $1.6 million grant to study the KDM5 family of transcriptional regulators, which—due to mutated KDM5 genes—are overproduced in a number of cancers including breast, colorectal and melanoma. In addition, KDM5 mutations account for about three percent of cases of intellectual disability that are linked to the X chromosome. Dr. Secombe is investigating how KDM5 proteins regulate gene activity by studying Drosophila (fruit flies), which possess one of the types of KDM5 protein capable of causing disease. A better understanding of how KDM5 proteins control gene expression could lead to new treatment strategies for KDM5-related cancers and for X-linked intellectual disability. Dr. Secombe is associate professor of genetics.

James C.M. Brust, M.D.Assessing a New TB Drug. The NIH has awarded James C. M. Brust, M.D., a five-year, $3.6 million grant to study bedaquiline – the first new tuberculosis (TB) drug to receive FDA approval in 40 years. Bedaquiline has not been well studied in patients with extensively drug-resistant (XDR) TB or in TB patients co-infected with HIV. The trial is taking place in South Africa—the epicenter of the convergent epidemics of drug-resistant TB and HIV. Dr. Brust and colleagues are examining drug-drug interactions between bedaquiline and antiretroviral therapy. Among participants who become resistant to bedaquiline, the researchers will use whole genome sequencing to identify the genetic mechanisms in TB bacteria responsible for resistance. In addition, bedaquiline is known to prolong the heart’s QT interval, increasing the risk for ventricular arrhythmia or sudden death. The researchers are therefore studying whether bedaquiline can be safely used with other QT-prolonging TB medications and antiretroviral therapy. Dr. Brust is associate professor of medicine at Einstein and attending physician, infectious diseases, Montefiore Health System.

Other New R01 Grants

Michelle H. Larsen, Ph.D.Rapid TB Test. As noted above, XDR TB is a particularly dire problem in South Africa, where many TB patients are co-infected with HIV. The lack of a rapid test to detect viable TB bacteria and determine their drug susceptibility has hampered efforts to improve survival of XDR-TB patients. The NIH has awarded Michelle Larsen, Ph.D., a four-year, $2.5-million grant to continue work on a promising human-sputum test that she and her colleagues have developed. The test uses two novel recombinant viruses that infect TB and cause viable TB to turn color and fluoresce; observing the fate of these bacteria in the presence of different drugs reveals which drugs are likely to be effective. By cutting weeks from the time it takes to assess which drugs will work, this rapid test could potentially reduce the spread of drug-resistant TB strains in communities. This work is done in collaboration with Dr. Alex Pym at the KwaZulu-Natal Research Institute for TB and HIV (K-RITH) in Durban, South Africa. Dr. Larsen is assistant professor of medicine and instructor of microbiology & immunology.

Hernando J. Sosa, Ph.D.Probing Protein Transporters. Proteins called kinesins use cytoskeletal highways to transport materials between different parts of the cell. The National Institute of General Medical Sciences has awarded Hernando Sosa, Ph.D., $1.6 million over four years to study how kinesins remodel the cytoskeleton. Dr. Sosa’s laboratory will employ advanced biophysical, computational and microscopic techniques to study the mechanism by which structural changes in certain kinesins influence microtubule depolymerization or stabilization. The kinesins chosen for study play key roles in fundamental cellular processes such as cell division, so a better understanding of their function could lead to new therapeutics for cancer and other diseases. Dr. Sosa is associate professor of physiology & biophysics.

Gary J. Schwartz, Ph.D.Combating Obesity. Through its ability to sense the amino acid leucine in the bloodstream, the mediobasal hypothalamus (MBH) at the base of the brain influences how much is eaten and the size of individual meals. In the Einstein-Mount Sinai Diabetes Research Center, Gary Schwartz, Ph.D., has shown in animal studies that leucine blood levels are rapidly elevated after a meal and that food intake can be reduced by keeping leucine available in the bloodstream by blocking its metabolism—a feed-back mechanism known to be disrupted in diet-induced obesity. In addition, he has identified two signaling pathways in MBH cells that mediate the MBH’s regulation of food intake. Dr. Schwartz has been awarded a four-year, $1.5-million NIH grant to further investigate the MBH’s novel nutrient-sensing abilities with the goal of developing effective anti-obesity therapies. Dr. Schwartz is professor in the Department of Medicine and the Dominick P. Purpura Department of Neuroscience.

Peng Wu, Ph.D.Protein Alterations and Cancer. Glycosylation—the addition of carbohydrate molecules called glycans--is the most common modification that cellular proteins undergo. The resulting glycoproteins are involved in most physiological processes—protein folding, receptor signaling and cell-cell adhesion, for example. Aberrant protein glycosylation occurs in cancer and almost all other major human diseases. Peng Wu, Ph.D., and
Ben Ovryn, Ph.D.Ben Ovryn, Ph.D., have received a four-year, $1.5-million NIH grant to analyze changes in naturally-occurring glycans that lead to cancer. This research will involve developing tools to image glycans in living cells and analyzing the roles of glycoproteins in cancer cells with the potential for metastasizing. Dr. Wu is associate professor of biochemistry and Dr. Ovryn is associate professor of anatomy & structural biology.

Richard N. Kitsis, M.D.Mitochondria and the Heart. Mitophagy—the selective elimination of mitochondria through autophagy—maintains cellular health by preventing dysfunctional mitochondria from accumulating. Heart-muscle cells require many mitochondria to generate the ATP to fuel ongoing cardiac contraction. For this reason, excessive mitophagy can damage the heart by inappropriately depleting “good” mitochondria. Richard Kitsis, M.D., made the surprising discovery that a protein called BAX, whose usual role is to promote cell death, functions to prevent excessive mitophagy in healthy heart muscle cells. BAX may restrain mitophagy by interacting with and inhibiting a second protein called PARKIN—which, in turn, appears to inhibit the cell death-inducing functions of BAX. Dr. Kitsis has received a $2.1-million, four-year NIH grant to investigate this bi-directional regulation between BAX and PARKIN. The findings may have implications for heart attack and heart failure. Dr. Kitsis is a professor of medicine and of cell biology, director of the Wilf Family Cardiovascular Research Institute and holds the Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease at Einstein and attending physician, cardiology, Montefiore Health System.

Nicholas E. S. Sibinga, M.D.Preventing Dangerous Plaques. Atherosclerosis—the buildup of plaques of fatty material inside arteries—is a major public health problem in Western societies. All too often, atherosclerosis culminates in the rupture of large, unstable plaques—the leading cause of heart attacks and strokes. Monocyte-derived macrophages and vascular smooth muscle cells are known to participate in the progressive buildup of arterial plaque. Nicholas E.S. Sibinga, M.D., was awarded a four-year, $2.1-million NIH grant to study the molecular mechanisms controlling the activities of those two cell types that contribute to plaque formation and eventual rupture. His goal is to find new ways to prevent plaques from expanding and weakening, so that their rupture can be prevented. Dr. Sibinga is an associate professor of medicine and of developmental & molecular biology at Einstein and attending physician, cardiology at Montefiore.