Department of Medicine Researchers Awarded NIH Grants

Esperanza Arias-Perez, Ph.D.

Autophagy Failure in Liver Cancer (R01)

Dr. Esperanza Arias-Perez and her team have found that chaperone-mediated autophagy (CMA) malfunction is involved in the progress of a form of nonalcoholic fatty liver disease, called nonalcoholic steatohepatitis, into liver cancer. CMA is a cellular quality control system that digests and recycles worn-out proteins. Defective CMA in the liver leads to hepatosteatosis (fatty liver) by altering liver glucose and lipid metabolism. The National Institute of Diabetes and Digestive and Kidney Diseases has awarded Dr. Arias-Perez a four-year grant to explore how the gradual decline of CMA in the steatotic liver facilitates transformation into malignant cells in the presence of a carcinogenic stimulus, and whether restoring normal CMA in the steatotic liver will prevent or slow down progression to liver cancer—a novel therapeutic approach. Dr. Arias-Perez is an assistant professor of medicine (hepatology). (1 R01 DK124308-01)

James Brust, MD (R01)

Understanding Risk of Resistance to New TB Drugs

In 2012, the U.S. Food and Drug Administration approved bedaquiline for treating drug-resistant tuberculosis—the first new type of TB drug approved in 40 years. Bedaquiline is administered in combination with at least four other drugs and has transformed the treatment of multidrug- and extensively drug-resistant (M/XDR) TB. However, combination therapy for M/XDR TB must last 1-2 years and is associated with many serious side effects. As a result, up to 25 percent of patients stop treatment early. Bedaquiline has a much longer half-life in the body than the drugs it’s combined with, so a halt in treatment means that bedaquiline persists alone in the bloodstream for many months. With other drugs no longer present to combat them, the TB bacteria can become resistant to bedaquiline.

James Brust, M.D., was awarded a five-year, $3.6 million grant from the National Institutes of Health (NIH) to investigate the development of resistance to bedaquiline after therapy with the drug is interrupted. The study involves a cohort of patients in South Africa with M/XDR TB— the largest bedaquiline treatment program in the world—and will address fundamental questions about bedaquiline pharmacology and resistance. The study includes collaborations with the University of Cape Town, Stellenbosch University and Emory University. Dr. Brust is an associate professor of medicine (general internal medicine) at Einstein and attending physician at Montefiore Health System. (R01AI145679)

John Chan, MD (R01)

Understanding TB Latency and Reactivation

Approximately one-fourth of the world’s population are infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), and a significant proportion of these individuals harbor latent bacilli that can reactivate to cause disease. This population thus constitutes a reservoir of dormant bacilli, which reactivation serves to propagate Mtb among humans. The precise mechanisms that regulate TB latency and reactivation remain unclear. Understanding such mechanisms can potentially lead to better control of TB. The National Institute of Allergy and Infectious Diseases has given Dr. John Chan a five-year grant to define the mechanisms that regulate tuberculous latency and reactivation. Dr. Chan will study how the interaction of Mtb Rv2623 (a universal stress protein) and Rv1747 (a putative ABC transporter) modulates bacillary growth in vivo to impact the development of Mtb latency and reactivation. Dr. Chan is a professor of medicine (infectious diseases) and of microbiology & immunology. Dr. Jordi Torrelles, PhD, a professor at the Texas Biomedical Research Institute, is Co-principal investigator on the grant. (1R01AI146340-01A1)

Nikolaos G. Frangogiannis, MD (R01)

Regulating TGF-β in Heart Failure and Remodeling

Heart muscle enlargement and thickening (remodeling) are hallmarks of the failing heart, and members of the transforming growth factor (TGF)-β superfamily are critically involved. The National Heart, Lung and Blood Institute has awarded Dr. Nikolaos Frangogiannis a four-year grant to investigate the endogenous mechanisms involved in blocking TGF-β superfamily signaling, which may prevent excess heart remodeling. Dr. Frangogiannis and his team will look specifically, and for the first time, at the role of the inhibitory proteins Smad6 and Smad7 in regulating heart muscle, connective tissue deposition, and immune cell activity in remodeling of the failing pressure-overloaded heart. They will perform in vivo experiments using cell-specific knockout mice together with in vitro loss- and gain-of-function studies to explore the role of the inhibitory Smads and to dissect their molecular targets. The proposed experiments may increase our understanding not only of TGF-β in heart failure and remodeling but of the biology of the TGF-β superfamily. Dr. Frangogiannis is professor of medicine (cardiology) and of microbiology & immunology. (1R01HL149407-01A1)

Nikolaos G. Frangogiannis, MD (R01)

Chemokines in Healing Myocardial Infarction

Members of the transforming growth factor (TGF)-β family are critically involved in regulating inflammation and in repairing damage after heart attack. But to avoid excess thickening of the heart muscle, these cytokines must stop their healing efforts at the right moment. The National Heart, Lung and Blood Institute has awarded Dr. Nikolaos Frangogiannis a four-year grant to investigate the mechanisms involved in suppressing and stopping TGF-β superfamily signaling cascades following infarction. He and his team will perform in vivo experiments using cell-specific knockout mice and in vitro loss- and gain-of-function studies to dissect the molecular signals that inhibit TGF-β responses in cardiomyocytes, fibroblasts, and macrophages, thus protecting the infarcted heart from adverse remodeling. Their unpublished preliminary data suggest an important role for two distinct mechanisms in negative regulation of TGF-β superfamily signaling. They involve cell-specific induction of the inhibitory Smads (I-Smads), Smad6 and Smad7 (two proteins that block the TGF-beta cascade through interactions with a wide range of intracellular signals) and the transmembrane pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor, which inhibits TGF-β signaling at least in part through interactions with I-Smads). Dr. Frangogiannis is professor of medicine (cardiology) and of microbiology & immunology. (2R01HL076246-17A1)

Viraj V. Patel, MD, MPH (R01)

Mobilizing HIV Prevention

Global health agencies have called for online interventions to engage populations at high HIV risk who are not being reached, but few effective models exist, and none exist in India, which is home to one of the world’s largest HIV epidemics, especially among SMM (sexual minority men). The National Institute of Mental Health has given Dr. Viraj Patel and his team a five-year grant to test a mHealth model to engage individuals at high HIV risk and increasing HIV testing and then linkage to either prevention or treatment. The behavioral intervention model (called CHALO! 2.0, which means “Let’s Go” in Hindi) will use mobile/social-networking platforms that includes virtual peer-support, educational outreach, and a digital coupon for free HIV testing. The scientific premise is that this community-developed, theory-based intervention will overcome traditional barriers and stigma to promote behavior change and linkage-to-care among SMM at high risk of HIV. The researchers will conduct a 18-month, three-arm randomized trial comparing CHALO! 2.0 to two different types of online control conditions, with the initial phase being completely virtual. This proposal addresses multiple goals of the NIH’s Office of AIDS Research, UNAIDS, and India’s National AIDS Control Organization. Dr. Patel is assistant professor of medicine (general internal medicine). (1R01MH119001-01A1)

Gaetano Santulli, MD, PhD (R01)

Diabetes and Beta Cell Calcium

Scientists know that know that pancreatic β cells secrete insulin after an influx of Ca2+. What mobilizes Ca2+ to enter the β cells is less understood. The NIH has given Dr. Gaetano Santulli a four-year grant to focus on IP3Rs (inositol 1,4,5-trisphosphate receptors), a main intracellular Ca2+ release channel. He and his team will test their hypothesis that IP3Rs play a key role in the pathophysiology of type 2 diabetes (T2DM), in which β cells become exhausted as they attempt to overcome insulin resistance. The team’s preliminary data show that IP3Rs are significantly upregulated in islets from T2DM patients compared with non-diabetic individuals and in mice fed a high-fat diet compared with non-diabetic littermates on standard chow. The researchers aim to define the role of β cell IP3Rs in developing T2DM and to identify the molecular mechanisms linking IP3Rs to pancreatic β cell dysfunction. This is the first investigation into the mechanistic role of a major intracellular calcium release channel within the pancreatic β cell in the pathogenesis of diabetes using a novel and β cell-specific murine model. Dr. Santulli is assistant professor of medicine (cardiology) and of molecular pharmacology. (1R01DK123259-01)

Nicolas Sibinga, MD (R01)

Gaining Insights into Vascular Remodeling

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Vascular remodeling—alterations in the structure of blood vessels—plays a key role during embryogenesis and in causing the vessel damage that occurs in atherosclerosis and other manifestations of CVD.

Vascular smooth muscle cells are the main drivers of vascular remodeling, but the mechanisms underlying smooth muscle cell activities—in particular, the roles played by mitochondria and metabolism—are not well understood. Studies conducted in the laboratory of Nicholas Sibinga, M.D., indicate that mitochondrial complex 1—the largest enzyme complex of the mitochondrial respiratory chain—regulates vascular smooth muscle cell behavior.

He has received a four-year, $2 million NIH grant to study mitochondria-mediated regulation of vascular wall function during embryogenesis and in mouse models of vascular disease in adulthood. His lab will use genetically modified mice and pharmacological strategies to characterize how mitochondrial function impinges on the vasculature in health and disease. The goal of the research is to identify vascular remodeling targets that are susceptible to drug intervention, resulting in enhanced health, increased lifespan, and reduced vascular disease disability. Dr. Sibinga is professor of medicine and of developmental and molecular biology at Einstein and a cardiologist at Montefiore. (1R01HL149921-01)

Rajat Singh, M.D., M.B.,B.S.

Alzheimer’s Disease and Metabolic Regulation in Aging (PO1)

Alzheimer’s disease and related dementias (AD/ADRD) are neurodegenerative disorders caused in part by protein damage in cells (proteotoxicity) and neuronal death. AD/ADRD is the sixth leading cause of mortality in the United States and affects approximately 5.4 million Americans. Due to AD/ADRD’s many and complex causes, research has yielded only marginal results. The National Institute on Aging has awarded Dr. Rajat Singh and his team funding to test two new hypotheses for restoring global metabolic function and preventing AD-related proteotoxicity. This project is part of a larger Program Project Grant of which, Dr. Ana Maria Cuervo is PI. It is known that AD-related proteotoxicity and aging overwhelm macroautophagy (MA), a cellular recycling program that degrades unwanted cytoplasmic contents, and that hypothalamic MA maintains glucose and energy metabolism. The researchers hypothesize that an early event in AD-related proteotoxicity is MA disruption in hypothalamic neurons, which then causes peripheral insulin resistance—in turn, accelerating the progression of AD/ADRD. They will study whether restoring overall metabolic function and preventing AD-related proteotoxicity by activating macroautophagy via diverse targeted and global approaches including a novel twice-a-day feeding intervention will delay cognitive decline. Dr. Singh is associate professor of medicine (endocrinology) and of molecular pharmacology. (2P01AG031782-13A1)

Fajun Yang, PhD (R01)

Finding the Molecular Glitches in Diabetes

Type 2 diabetes is widespread in the United States and worldwide. As type 2 diabetes progresses, the body’s impaired response to insulin (insulin resistance) results in chronically elevated blood sugar levels (hyperglycemia). A better understanding of the causative underlying molecular mechanisms could lead to more effective treatments. The National Institute of Diabetes and Digestive and Kidney Disease has awarded Fajun Yang, Ph.D., a four-year, $2 million grant to study the Mediator complex—an important regulator of metabolism that appears to connect many transcription factors (proteins that regulate gene expression) to RNA polymerase II, an enzyme that catalyzes transcription. Dr. Yang and colleagues previously found that MED15, a subunit of the Mediator complex, interacts with the transcription factor GATA4 in the liver to activate gluconeogenesis (production of glucose from non-carbohydrate substrates), leading to insulin resistance in mice. Findings from the research could lead to novel interventions for treating type 2 diabetes. Dr. Yang is associate professor of medicine and of developmental and molecular biology at Einstein. (1R01DK117417-01)

Anna Bortnick, MD (K23)

Preventing Cardiac Calcification

Centenarians and their offspring enjoy a lower rate of cardiovascular disease than people with usual longevity. Dr. Anna Bortnick has received a five-year grant from the National Heart, Lung and Blood Institute to study the mechanisms of this protection. Because cholesterol and lipid deposition are a potent trigger for calcification, she and her team propose that exceptionally long-lived people have more efficient cholesterol efflux—the release of cholesterol from cardiac tissues to serum. Cholesterol efflux is the first step in reverse cholesterol transport and may protect against the calcification of the coronary arteries and aortic valve associated with myocardial infarction, congestive heart failure, and stroke. Dr. Bortnick and her team will measure coronary artery and aortic valve calcification by computed tomography and cholesterol efflux in the Einstein LonGenity study cohort of up to 1400 genetically homogenous older Ashkenazi Jewish adults. The researchers aim to relate longevity with reduced calcification and improved cholesterol efflux capacity, and to identify genetic variants underlying these phenotypes. This study may help identify key pathways that could become targets of small molecules to protect against calcification, providing new prevention approaches to cardiovascular disorders that are currently untreatable. Dr. Bortnick is assistant professor of medicine (geriatrics). (1K23HL146982-01A1)

Kerry J. Murphy, MD (K23)

HIV and the Aging in Women

HIV may be associated with premature aging in the female genital tract, including abnormal changes in the vaginal microbiome (dysbiosis) and mucosal inflammation, which may increase the risk of vaginal atrophy and genital tract infections. Dr. Kerry Murphy has received a four-year grant from the National Institute on Aging to study the association between HIV and accelerated genital tract aging in 50 menopausal women living with HIV (WLWH) and 50 HIV uninfected menopausal women. The coating of bacteria with antibodies may play a role in accelerated genital tract aging. Dr. Murphy hypothesizes that bacterial coating may be protective but reduced in the setting of HIV and dysbiosis. She will use a novel technique of flow cytometry based bacterial cell sorting and 16S rRNA sequencing to characterize immunoglobulin (Ig) coating of bacteria. She hypothesizes that menopausal WLWH develop genital tract aging earlier and that the magnitude of difference in aging biomarkers, including increased dysbiosis, less bacterial Ig coating, and increased mucosal inflammation will be greater in younger and older menopausal WLWH than in younger and older menopausal women without HIV. Because estrogen has not been studied in menopausal WLWH, she will conduct a randomized clinical trial to assess whether vaginal estradiol treatment results in a more optimal Ig coated vaginal microbiome, reduced mucosal inflammation, and improved symptoms compared to WLWH who do not receive vaginal estradiol treatment. Dr. Murphy is assistant professor of medicine (infectious diseases). (1K23AG062400-01A1)

Angela Lombardi, PhD (KL2)

A translational approach to identify cutting-edge therapeutic strategies in type 1 diabetes

Type 1 diabetes (T1D) is one of the most common autoimmune endocrine disorders associated with significant morbidity and mortality in children and adults. There is currently no cure for T1D, and the only available treatment is insulin replacement which, though life-saving, is costly and associated with often fatal high or low glucose levels. The NIH-Clinical and Translational Science Award Program and the Einstein/Montefiore Institute for Clinical and Translational Research has given Dr. Angela Lombardi a three-year grant to explore novel strategies to treat or prevent autoimmunity in T1D. In her study she proposes to block antigen presentation using novel D-amino acid peptides (D-peptides), specifically by blocking the HLA-DQ8/2 peptide binding pocket from presenting diabetogenic peptides to autoreactive T-cells. She hypothesizes that D-peptides will reduce or eliminate the need for insulin replacement therapy and since this approach is specific to the cause of T1D, it should not cause general immunosuppression. Her preliminary data show promising results for two D-peptides, able to block T-cell activation in humanized mice and in peripheral blood mononuclear cells isolated from patients with T1D. This is the first study seeking to develop a D-peptide to treat T1D; the approach may also apply to other autoimmune diseases (such as celiac disease) carrying HLA-DQ8 or other HLA class II alleles. Dr. Lombardi is research assistant professor of medicine (endocrinology) and of microbiology and immunology at Einstein. (1KL2TR002558)