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Endocrine Fellows’ Research Opportunities Mentor: Christoph Buettner, M.D. Phone: 212-241-3425 E-mail: [email protected] Basic science projects: Background: Our interest is to understand how hormones and nutrients are sensed by the hyopothalamus and how the brain controls systemic metabolism. In the insulin resistant state and in type 2 diabetes, this brain control of metabolism is impaired and we believe this dysfunction plays an important role in the pathogenesis of both of these conditions. Impaired metabolic control is associated with a pro-inflammatory state. We have found that hormones like insulin and leptin regulate systemic inflammation via the brain and the autonomic nervous system and speculate that this may be the basis for the link between impaired metabolic control and inflammation. We study insulin action through clamp studies in rodents to analyze lipid and glucose fluxes and combine these with signaling studies, PCR, biochemical anaylsis to understand the molecular events that mediate this brain control of metabolism and innate immunity. Projects: 1. Anti-inflammatory effects of brain insulin signaling: Can we improve survival in sepsis by infusing insulin only in the brain or vice versa by altering adipose tissue function? 2. Regulation of adipose tissue or liver metabolism through the CNS 3. Role of the sympathetic nervous system in regulating energy homeostasis and nutrient fluxes using novel mouse models of genetic denervation. 4. Role of alcohol consumption/binge drinking in insulin resistance and the metabolic syndrome Mentor: Terry F. Davies, M.D., FRCP Phone: 646 436 2972 E-mail: [email protected] Thyroid Research Laboratory at the James J. Peters VA Medical Center Our group is highly focused on thyroid cell biology and thyroid autoimmunity using both patients and mice as models for our studies. We are particularly interested in the TSH receptor in both the clinical and laboratory setting and are examining its structure, function, immunogenicity and its role in thyroid cancer. Currently we are highly focused on thyroid stem cells and thyroid active small molecules. Please review our papers in PubMed. Note that we are well funded and can afford to send fellows on travel to learn new techniques and to attend conferences. Here are some examples of opportunities for Clinical Fellows in 2015: 1, Human stem cells – We have produced human thyroid follicles from human thyroid stem cells and are in the process of fully characterizing them. We have projects focused on examining the role of growth factors on their development. 2. TSH receptor antibodies – We are interested in the neutral variety of TSHR-Abs and now have monoclonal neutrals to treat mice in vivo and examine the thyroid responses. 3. .Small molecules interacting with the TSH receptor as potential therapeutics We have identified potent small molecules which activate the TSH receptor. We now envisage projects in mice using these molecules to stimulate their thyroid glands. Clinical fellows working with us have been enormously successful in terms of publications and a good many have gone on to academic careers with which you may already be familiar. We do prefer our research Fellows to have an academic bent, to consider an academic career as a real option, and to have the perseverance to make research successful. Right now, the VA system is ideal for launching careers because of the junior grant programs available and the cutting edge nature of our research programs. We invite you to visit our modern laboratory facility and meet with the group at any time and to visit our web site: http://NYThyroid.com Mentor: Eliza Geer, M.D. Phone: 212-241-6139 E-mail: [email protected] October 2012 My research currently includes the studies outlined below, but I am interested conducting any clinical/translational project related to pituitary diseases, and the Mount Sinai Pituitary Care and Research Center has the patient population to support projects on any pituitary disease/tumor type. See the Pituitary Research Program website for more information: www.icahn.mssm.edu/pituitary Ongoing studies: - - - Body Composition and the Metabolic Syndrome in Cushing’s disease. This is a longitudinal cohort study currently with over 60 prospectively enrolled Cushing’s patients. It includes a number of sub-aims, including investigations of body composition; appetite; mood; proinflammatory markers; epigenetic modifications and expression of glucocorticoid sensitive genes; and measurements of lipolysis and lipogenesis in a fat biopsy taken from patients with active and treated Cushing’s disease and matched controls. We evaluate patients with newly diagnosed Cushing’s disease before and again over time after treatment. Visits are conducted at the Clinical Research Unit. Long Term Risk of Treated Cushing’s Disease. This is a large database of over 400 patients with Cushing’s. Information from this database has already generated 2 publications, and it continues to be a valuable resource for multiple future studies. Questions that could potentially be answered with this databased include for example: How effective is gamma knife or fractionated radiation therapy for the treatment of Cushing’s? What is the role of midnight salivary cortisol measurements is diagnosing recurrence in Cushing’s? Pathogenesis of Corticotroph Tumor Development. This study conducts somatic and germline whole exome sequencing in a rare family with inherited Cushing’s. Characterization of Treatment and Outcomes in patents with prolactinomas: Large database and cross-sectional study on treatment outcomes in patients with prolactinomas. - Clinical trials: We currently have 4 ongoing trials investigating new medical therapies for patients with acromegaly and Cushing’s disease. These studies would not be the primary project for an endocrine fellow, but fellows can get involved if interested: o Pasireotide LAR treatment for Cushing’s Disease: Phase 111b trial that measures efficacy of this new somatostatin analogue as treatment for persistent/recurrent CD o An ACromegaly, open-label, multi-CEnter, Safety monitoring program for treating patients with SOM230 (pasireotide) LAR (ACCESS) o An Open-label study to assess the safety and efficacy of COR-003 (2S, 4RKetoconazole) in the treatment of endogenous Cushing’s Syndrome o A Phase III, multi-center, double-blind, randomized withdrawal study of LCI699 to evaluate the safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease Potential future studies: - Characterization of sustained Cushing’s disease remission: Cross-sectional study to characterize sub-types of CD remission. What is the optimal glucocorticoid treatment regimen for treating Ipilimumab induced hypophysitis? Study of cardiovascular risk or optimal endocrine replacement for patients with panhypopituitarism Neuroimaging study in Cushing’s disease Mentor: Derek LeRoith, M.D. Phone: 212-241-6306 E-mail: [email protected] Co-Mentor: Emily Gallagher, MD Phone: 212-241-1954 Email: [email protected] Epidemiological studies have shown that obese women, those with diabetes, and the metabolic syndrome are more likely to develop and die from breast cancer than women without these conditions. Our group focuses on the increased risk of breast cancer development and mortality associated with type 2 diabetes. Clinical projects: 1. To study the relationship of the metabolic syndrome/prediabetes and breast cancer in women with different racial backgrounds. African American women have higher rates of type 2 diabetes than white women. Additionally, African American women are more likely to die from breast cancer than white women. Women with insulin resistance and hyperinsulinemia, the metabolic syndrome and type 2 diabetes have a higher breast cancer mortality than those without type 2 diabetes. In collaboration with the Division of Internal Medicine and Health Policy we are currently conducting a multi-site study on African American and white women with breast cancer to determine whether the racial differences in breast cancer mortality are due to differences in insulin resistance and insulin signaling within the tumors. We will be collecting anthropometric data from patients, blood samples and tumor samples. We will determine whether insulin resistance is associated with tumor stage, prognosis and insulin signaling in the tumors. Basic Science Projects 1. Type 2 diabetes and breast cancer in a mouse model. We also have a mouse model of insulin resistance and are using this model to understand the mechanisms through which hyperinsulinemia is driving tumor growth and metastases. Our future projects will involve using human estrogen receptor positive and negative tumors in immunodeficient insulin resistant mice, examining the interaction between the stromal tissue surrounding the tumor and the tumor itself in breast cancer and determining the role of the insulin receptors. 2. The role of hypercholesterolemia and cancer growth and metastases. Dyslipidemia has also been shown in human studies be increase tumor growth. The mouse model with hypercholesterolemia is used to study the effect of hyperlipidemia and increased cancer risk and mortality. Mentor Alice C. Levine, M.D. Phone: 212-241-7509 E-mail: [email protected] 1. Prostate. Dr. Levine’s lab focuses on basic science research in the field of prostate cancer. Specifically, her group is involved in stromal-epithelial interactions in the normal and neoplastic prostate as well as stromal-epithelial interactions between prostate cancer and bone cells in metastatic sites. They have previously published on the role of steroid hormones, cytokines, cyclooxygenase-2 and Wnt signaling in these interactions in tissue culture and animal models. Dr. Levine has had many student, resident and post-doctoral trainees in her lab over the past 20 years, who have become expert in the techniques of immunohistochemistry, cell culture, Western blot, RT-PCR and in vivo tumor passaging. They have also presented at National Meetings and co-authored publications in fields of steroid hormone, breast and prostate cancer research. Project: Fellow would work on the mechanisms of prostate cancer bone metastases and the development of new drugs to prevent and treat these metastases. 2. Adrenal. Dr. Levine is Co-Director of the Adrenal center and there are several clinical translational projects that can be developed under her mentorship in this area. Currently. Dr. Aarti Ravikumar (Second Year Endocrine Fellow) is conducting a clinical research project, “Glucocorticoid Receptor Blockade with Mifepristone in Patients with Mild Adrenal Hypercortisolism” which is IRB approved, HS#: 13-00548 GCO#1: 13-1061(0001) MSSM. In addition, Dr. Levine is conducting a translational research study investigating the expression of LH/hCG receptor and other proteins in human adrenal cortical tissues. Personnel: The Levine laboratory is staffed by Shen Yao, M.D., Senior Research Technician, Alexander Kirschenbaum, M.D.,(Urologist/consultant) and Dr. Levine. Lab Meetings: Weekly group lab meetings are held on Thursday mornings, as well as more informal daily meetings regarding experimental design, interpretation and troubleshooting on all clinical and basic research projects. Mentor: Carol J. Levy, MD, CDE Phone: 212-241-0068 E-mail: [email protected] My current clinical research interests are in the areas of type 1 diabetes and diabetes in pregnancy. Active research projects are listed below: 1. Use of an artificial pancreas in the outpatient setting: current studies utilize the DiAs system in collaboration with UVA in the outpatient setting for patients with type 1 DM 2. Study of Fia Aspart in type 1 DM-a phase 3 study comparing Fia aspart (an ultra rapid insulin analog) in comparison to aspart to treat patient on MDI with type 1 DM 3. Liraglutide in type 1 DM - a multicenter trial placebo controlled evaluating liraglutide for the adjunctive treatment of type 1 dm 4. PERL study- multicenter NIH study investigating the use of allopurinol as adjunctive therapy with ACEI therapy for patient with type 1 DM and early nephropathy GFR studies to be done in the GCRC at Mount Sinai 5. Trial Net- NIH study evaluating the natural history of the development of type 1 DM 6. HGF and its role in GDM-collaborative project with DOMI and OB evaluating the role of hepatocyte growth factor in GDM both clinical and lab work opportunities Future projects: 1. Further artificial pancreas studies evaluating the impact of the DiAs system in pts with hypo unawareness 2. Use the DiAs in full closed loop for several months in the at home setting 3. Collaboration with RPI in further artificial pancreas studies 4. Collaborative projects with obstetrics in GDM (including use of fructosamine as a postpartum screening tool for GDM) Opportunities to develop additional projects also exist including studies in type 2 DM Mentor: Maria New, M.D. Phone: 212-241-7847 E-mail: [email protected] 1. Hypothesis: Hyperandrogenemia resulting from congenital adrenal hyperplasia has a different metabolic outcome from the hyperandrogenemia of PCO. We would like to study the metabolic outcome of hyperandrogenemia associated with CAH, particularly hyperinsulinism, obesity, and lipid metabolism. I know that there has been a great deal of work on the metabolic outcome of hyperandrogenemia in PCO, but there are no reports of the metabolic outcome of hyperandrogenemia in congenital adrenal hyperplasia. 2. Hypothesis: Steroid 21-hydroxylase deficiency is rare in Sephardic Jews. The very high frequency of 21-hydroxylase deficiency in Eastern European Jews (Ashkenazi) is well documented. However, the frequency in Sephardic Jews is unknown. Plan: to recruit and study Sephardic Jews and do DNA analyses for non-classical 21hydroxylase deficiency (NC21OHD) either by blood DNA, or by buccal smear DNA. Determine the frequency of 21-hydroxylase deficiency in Sephardic Jews by both hormonal and genetic measures. 3. Hypothesis: Impaired fertility in males with non-classical 21-hydroxylase deficiency is reversible within 3 months of treatment with dexamethasone. In clinic define NC21OHD hormonally and genetically in male patients who have impaired fertility. Study the reversal of impaired fertility by sperm counts and hormonal measures after treatment with dexamethasone. 4. Hypothesis: PCO arises in adults who have NC21OHD in early life. We will examine the frequency of PCO in female patients with NC21OHD. Is there another risk factor if the androgens are well suppressed and yet PCO develops? 5. Hypothesis: Treatment of a steroidogenic defect of 21-hydroxylation corrects frontal hair loss and irregular periods in women. Determine the interval of time required for the remission of irregular periods and frontal hair loss in females with congenital adrenal hyperplasia. Contrast the outcome of treatment on frontal hair loss and irregular menses. 6. Hypothesis: Hyperandrogenemia in women is of ovarian origin more frequently than of adrenal origin in women. Conduct clinical studies of patients with intersex conditions to determine the diagnosis. This will include hormonal and genetic studies of steroidogenesis and steroid receptor defects. Fellows will attend clinic to learn how to define the intersex condition, assign Prader scores, describe the genital ambiguity and estimate the origin of the androgens by ACTH stimulation and dexamethasone suppression. List of Projects for Fellows and Volunteers: All of these studies have been mentored and supervised by Dr. Maria New 1. What is the outcome in elderly CAH patients? (older than 25 years) This has been submitted as a potential article in the Journal of International Endocrinology. (A physician applying for residency, Bushra Javed, MD completed this study during the summer as a volunteer) 2. Describe patients who temporarily lose salt wasting aspect of their disease and then regain it. A protocol has been written for this study by a future fellow. 3. Describe patients who temporarily lose hormonal evidence of CAH, e.g. increased 17-OHP and then later regain it. A protocol has been written for this study by a future fellow. 4. Describe patients who have a T insertion in Exon 7. What is their phenotype? (Wellesley college student, Meredith Roy, as a volunteer has completed this research this summer. Tony Yuen, PhD, our lab supervisor is preparing this for publication with Meredith.) 5. Describe patients who have a low birth weight. What is the outcome of their growth? How long does it take for them to catch up? (A high school student, Allie Weiller, as a volunteer undertook this study and completed it this summer.) 6. Describe the reversal of impaired fertility in patients with nonclassical 21-OHD when they are treated with dexamethasone. A protocol has been written for this study by a future fellow funded by the Genesis grant. 7. Describe Russian Jews with nonclassical 21OHD we treat to reverse infertility. A protocol has been written for this study by a future fellow funded by the Genesis grant. 8. An assistant professor from Croatia, Katja Dumic, as a volunteer studied this summer with lab supervisor, Tony Yuen, PhD to learn new methods of sequencing the gene CYP21A2. 9. Two junior faculty members are writing NIH proposals. Dr. Ahmed Khattab is evaluating genotype-phenotype disconcordance within families and Dr. Mabel Yau is studying the long range outcomes of apparent mineralocorticoid excess and performing genetic analysis on AME patients in Oman. 10. As of summer 2011, Dr. New has entered into a scientific collaboration with Dr. Dennis Lo of the Chinese University of Hong Kong medical school to study a new method of noninvasive prenatal diagnosis of congenital adrenal hyperplasia (CAH). This study will be funded by a Chinese government grant, the PI of which is Dr. Lo. Dr. Lo is the discoverer of the presence of fetal DNA in maternal blood at 6-7 weeks of gestation. He has a long track record of utilizing fetal DNA in diagnosing genetic disorders prenatally, and Dr. New and Dr. Lo will work together using this new methodology to make genetic analysis of fetal DNA in maternal blood, which will be early enough for decisions about prenatal treatment of congenital adrenal hyperplasia. The entire adrenal steroid disorders team will be working on this Chinese-American collaborative grant for which a contract has just been written by the Mount Sinai GCO. Mentor: Maria Skamagas, M.D. Phone: 212 241 3412 Email: [email protected] Maria Skamagas, M.D. is the bone expert and endocrine consultant on a recently funded NIH study (P.I. Andrea Branch, Ph.D.) on the impact of Vitamin D therapy on bone, inflammation and metabolic markers and parameters in patients with HIV/AIDS. Second Year Endocrine Fellow could work with Dr. Skamagas to work on one aspect of this study. ABSTRACT. In the post-HAART era, patients continue to suffer from the adverse medical consequences of HIV/AIDS. The adverse effects include incomplete immune reconstitution, chronic inflammation, depression, increased risk of cardiovascular and metabolic disease, and low bone density. Clinical trials suggest that vitamin D supplements can increase bone density, reduce inflammation, alleviate depression, and increase longevity if given in adequate doses. To achieve maximum benefits, most vitamin D experts agree that vitamin D treatments should raise the concentration of 25hydroxyvitamin D [25(OH)D] above 30 ng/ml. A growing number of HIV care providers desire an evidence-based protocol for achieving these 25(OH)D target levels. This project addresses the need for a validated protocol for treating vitamin D deficiency in HIV-positive individuals on HAART. The goal of Aim I is to conduct a 12-mo randomized, double-blinded trial comparing two dosing regimens of oral vitamin D plus 0.5 g/d of calcium in patients on stable HAART who have 25(OH)D levels ≤ 25 ng/ml and undetectable HIV viral load at baseline (100 per arm). Medication event monitoring system (MEMS) caps will be used to record supplement use and to promote adherence. Subjects in Protocol A will receive 50,000 IU/wk of vitamin D2 for 8 wk followed by 1000 IU/d of vitamin D3 for 48 wk. Subjects in Protocol B will receive 2000-4000 IU/d of vitamin D3, depending on the basal 25(OH)D level, with dose titration, as necessary, based on the slope of the initial response. The primary outcome measure is the difference in the percentage of subjects with 25(OH)D levels in the range of 30-60 ng/ml at 12 mo. The secondary outcome is the slope of the 25(OH)D response curve during various time intervals. The goal of Aim II is to compare the impact of the two protocols on markers of disease. The primary outcome measure is the change in the CD4+T cell count. Secondary outcomes include changes in CD4+ T cell subsets, markers of inflammation, markers of bone and calcium metabolism, self-reported psychological status, viral load, side effects, safety, and adherence. To our knowledge, this trial is the first head-to-head comparison of a regimen that uses a loading dose of vitamin D2 with a regimen that uses a tiered starting dose of vitamin D3. The project will yield a validated protocol for treating vitamin D deficiency in HIV-infected patients on HAART and will provide initial data about the risks and health benefits of vitamin D and calcium supplements. This information is essential for designing definitive multicenter trials in the future. Mentor: Andrew F. Stewart MD Phone: 212-241-5171 E-mail: [email protected] Director, Diabetes, Obesity and Metabolism Institute Our group, which includes Adolfo Garcia-Ocaña PhD, Rupangi C. Vasavada PhD, Nathalie Fiaschi-Taesch PhD and Donald K. Scott PhD and myself as senior faculty, focuses on regeneration for rodent and human pancreatic beta cells for the treatment of both Types 1 and 2 diabetes. We moved from the University of Pittsburgh to MSSM in October, 2012. While it is well known that Type 1 diabetes results from beta cell deficiency, it has only recently been appreciated through autopsy and GWAS studies that this applies to Type 2 diabetes as well. Our work encompasses rodent, human, molecular, cell biological and genomic approaches to beta cell loss and regeneration in both Type 1 and Type 2 diabetes. The program has links to other Institutes at MSSM including Genomics and Bioinformatics, Immunology, Development, Cardiovascular, Personalized Medicine, Bariatric Surgery, the Clinical Research Center, and others. Our work is supported by the NIH, NIDDK and the Juvenile Diabetes Research Foundation (JDRF). We have a long and successful experience in training clinical postdocs in clinical and basic research. We welcome experienced as well new, aspiring inexperienced MD and PhD fellows and student researchers with an interest in diabetes. Recent Publications: 1. Cozar-Castellano I, Harb G, Selk K, Takane KK, Vasavada RC, Sicari B, Law B, Zhang P, Scott DK, Fiaschi-Taesch N, Stewart AF. Lessons from the Comprehensive Molecular Characterization of Cell Cycle Control in Rodent Insulinoma Cell Lines. Diabetes 57:3056-68, 2008. PubMed ID: 18650366 2. Fiaschi-Taesch NM, Bigatel TA, Sicari BM, Takane KK, Velazquez-Garcia S, Harb G, Karen Selk K, Cozar-Castellano I, Stewart AF. A Survey of the Human Pancreatic Beta Cell G1/S Proteome Reveals a Potential Therapeutic Role for Cdk-6 and Cyclin D1 in Enhancing Human Beta Cell Replication and Function in Vivo. Diabetes 58:882-93, 2009. PubMed ID: 19136653 3. Fiaschi-Taesch NM, Salim F, Kleinberger J, Cozar-Castellano I, Selk K, Cherok E, Takane KK, Stewart AF. Induction of Human Beta Cell Proliferation and Engraftment Using A Single G1/S Regulatory Molecule, Cdk6. Diabetes 59:1926-36, 2010. PMIID:20668249 4. Karslioglu E, Kleinberger J, Salim F, Cox A, Takane KK, Donald K. Scott DK, Stewart AF. cMyc is the principal upstream driver of beta cell proliferation in rat insulinoma cell lines and Is an effective mediator of human beta cell replication. Mol Endocrinology 25:17605. Takane KK, Kleinberger J, Salim F, Fiaschi-Taesch NM, Scott DK, Stewart AF. Regulated and reversible induction of adult human beta cell replication. Diabetes 61:418-24, 2012. PMID: 22210317 6. Kulkarni RN, Bernal-Mizrachi E, Garcia-Ocaña A, Stewart AF. Human ß-Cell Proliferation and Intracellular Signaling: Driving in the Dark Without a Roadmap. Diabetes 61:2205-2213, 2012. PMID: 22751699 7. Fiaschi-Taesch N, Kleinberger JW, Salim F, Troxell R, Cox AE, Takane KK, Scott DK, Stewart AF. Developing A Human Pancreatic Beta Cell G1/S Molecule Atlas. Diabetes 62:2450-59, 2013. PMID 23493570. PMC3712053. 8. Fiaschi-Taesch NM, Kleinberger JW, Salim F, Troxell R, Cox AE, Takane KK, Srinivas H, Scott DK, Stewart AF. Cytoplasmic-Nuclear Trafficking of G1/S Cell Cycle Molecules and Adult Human Beta Cell Replication: A Revised Model of Human Beta Cell G1/S Control. Diabetes 62:2460-70, 2013. PMID 23493571. PMC3712040. 9. Bernal-Mizrachi E, Kulkarni RN, Stewart AF, Garcia-Ocaña A. Human β-Cell Proliferation and Intracellular Signaling Part 2: Still Driving in the Dark without a Roadmap. Diabetes 63:819-31, 2014. PMID 24556859 PMCID 3931400 10. Garcia-Ocana A, Stewart AF. “RAS”ling beta cells to proliferate for diabetes: why do we need MEN? J Clin Invest. 124:3698-700, 2014. PMID 25133422. 11. Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, Garcia-Ocana A, Stewart AF. Advances and Challenges in Human Beta Cell Proliferation for Diabetes. Nature Reviews in Endocrinology (in press) 2014. 12. Wang P, Felsenfeld DP, Liu H, Sivendran S, Bender A, Alvarez-Perez JC, Garcia-Ocana A, Sanchez R, Scott DK, Stewart AF. Induction of Rodent and Human Pancreatic Beta Cell Replication By Inhibitors of Dual Specificity, Tyrosine-Regulated Kinase 1a. Nature Medicine (in revision), 2014. Mentor Ronald Tamler, M.D. Phone: 212-241- 3436 E-mail: [email protected] Title: mHealth in Diabetes Self-management Background: Diabetes is a chronic disease, and as such depends on successful selfmanagement by the patient. The urban population has been leapfrogging the PC and has rapidly adopted smartphones. Mobile Health (also called mHealth) lets clinicians create tools to improve adherence to medications, office visits, diet and blood glucose logging. In Diabetes Care of September 2011, a mobile health intervention led to A1c reduction of 1.9%. Plan: Build and app, study its usability and investigate whether it affects DM control. The app is almost done, and the project needs to be resubmitted to the IRB for approval. We already presented survey results of our patient and physician population at ENDO. The smartphone application should be piloted and studied in a select number of patients and further optimized based on their feedback in focus groups. Subsequently, a more mature version will be used in a prospective 3 month trial. Results include: Questionnaire responses, BG downloads, A1c, number of hospitalizations compared to a matched control group etc. The fellow will be responsible for conducting most of the research and be the driving force for application development. This is a great project and Gillian got to present at ENDO conference last summer. Please email me to set up a meeting if interested. Title: Effect of online training on inpatient glycemia In 2008-2010, we designed and administered a successful project on inpatient diabetes management, initially to medicine residents, and then to hospitalists. The intervention resulted in lower patient blood glucose, better knowledge and confidence of participants, and 4 publications. We have license to use an updated version of the course at MSH. In addition to medicine residents, we can target other providers in the hospitals, like NPs, cardiologists, etc. The project is to establish and analyze patient BG changes and participant knowledge data. Mentor: Yaron Tomer, MD, FACP, FACE Phone: 212-241-5461 E-mail: [email protected] Dr. Tomer’s research focuses on the mechanisms causing thyroid autoimmunity, including Grave’s disease and Hashimoto’s thyroiditis, and on the etiology of autoimmune diabetes. There are several projects available in his lab currently: 1. Gene mapping in AITD – this project focuses on identifying genes that are associated with autoimmune thyroid diseases (Graves’ and Hashimoto’s diseases). 2. Gene mapping in AITD+T1D – this project focuses on identifying genes that predispose individuals to develop both type 1 diabetes (T1D) and AITD. This combined phenotype is considered a variant of the autoimmune polyglandular syndrome type 3 (APS3). 3. Gene function – several projects are aimed at identifying the mechanisms by which gene variants that have been found to be associated with AITD or APS3 predispose to disease. The genes studied include: HLA-DR, CD40, CTLA-4, thyroglobulin, TSH receptor, and FOXP3. 4. Environmental causes of AITD – this project focuses on the mechanisms by which chronic hepatitis C virus infection as well as interferon alpha treatment of HCV infection may precipitate thyroiditis. The above projects involve in vitro studies using tissue cultures and cell lines, in vivo studies using mouse models and transgenic mice, and human studies (for gene identification). Mentor: Rupangi C. Vasavada PhD Phone: 212-241-2839 E-mail: [email protected] Diabetes is one of the fastest growing diseases worldwide, with an immense economic and health burden attached. It is now well accepted that all forms of diabetes result from a deficiency of insulin-producing functional pancreatic beta cells. Therefore, research in my lab is directed towards finding ways to induce the growth, survival, and regeneration of functioning pancreatic beta cells. We have focused on the role of growth factors and the signaling and molecular pathways through which they mediate their effects in normal pancreatic beta cell physiology and in the pathophysiological settings of diabetes and islet transplantation. The translational goals of our research are: i) to induce human beta cell growth and function including in the setting of islet transplants; ii) to induce beta cell regeneration in vivo; iii) and to improve outcomes in animal models of type 1 and/or type 2 diabetes, either through the acute use of these growth factors or downstream target molecules activated by these factors. The ultimate objective of the research is to find ways to enhance preservation and regeneration of functional beta cells in vivo, for the treatment of diabetes. Specific projects in the lab include: 1) To examine the physiological and pathophysiological role of a bone-related molecule, Osteoprotegerin (OPG) in the regulation of pancreatic beta cell growth and survival in rodent models and in human beta cells. 2) To understand the mechanism of OPG action in the beta cell, specifically evaluating its downstream pathways, RANKL/RANK and TRAIL/DR, in the beta cell. 3) To assess the potential of repurposing the osteoporosis drug, Denosumab, for the treatment of diabetes in animal models, and more importantly, in patients in future. 4) To evaluate the therapeutic potential of lactogens for the treatment of type 1 diabetes. 5) Understand the actions of parathyroid hormone-related protein (PTHrP) in human beta cells. Recent Publications: 1. Guthalu NK, Joshi-Gokhale S, Harb G, Williams K, Zhang XY, Takane KK, Zhang P, Scott D, Stewart AF, Garcia-Ocaña A, Vasavada RC. Parathyroid hormone-related protein (PTHrP) enhances human β-cell proliferation and function with simultaneous induction of cyclindependent-kinase 2 (cdk2) and CyclinE expression. Diabetes 59: 3131-3138 (2010). PMID: 20876711 2. Williams K, Abanquah D, Joshi-Gokhale S, Otero A, Lin H, Guthalu NK, Zhang XY, Mozar A, Bisello A, Stewart AF, Garcia-Ocaña A, Vasavada RC. Systemic and acute administration of parathyroid hormone-related peptide 1-36 stimulates endogenous beta cell proliferation while preserving function in adult mice. Diabetologia 54:2867-2877 (2011). PMID: 21800111 3. Guthalu NK, Mozar A, Otero A, Chin C, Garcia-Ocaña A, Vasavada RC. Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Jak2/Stat5 signaling. Diabetologia 55:1721-1732 (2012). PMID: 22382519 4. Alvarez-Perez JC, Ernst S, Demirci C, Casinelli GP, Mellado-Gil JM, Rausell-Palamos F, 5. 6. 7. 8. Vasavada RC, Garcia-Ocaña A. Hepatocyte Growth Factor/c-Met Signaling Is Required for Beta-Cell Regeneration. Diabetes 63:216-223 (2014). PMID: 24089510 Mozar A*, Guthalu NK*, Pollack I, Fenutria R, Vasavada RC. The role of PTHrP in pancreatic beta cells and implications for diabetes pathophysiology and treatment. Clinical Reviews in Bone and Mineral Metabolism 12:165-177 (2014). Alvarez-Perez JC, Rosa TC, Casinelli GP, Valle SR, Lakshmipathi J, Rosselot C, RausellPalamos F, Vasavada RC, Garcia-Ocaña A. Hepatocyte growth factor (HGF) ameliorates hyperglycemia and corrects ß-cell mass in IRS2 deficient mice. Molecular Endocrinology (2014, in press). PMID:25361392 Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, Garcia-Ocana A, Stewart AF. Advances and Challenges in Human Beta Cell Proliferation for Diabetes. Nature Reviews in Endocrinology (2014, in press). Guthalu NK, Fenutria R, Pollack I, Orthofer M, Garcia-Ocaña A, Penninger J, Vasavada RC. Osteoprotegerin and Denosumab stimulate human beta cell proliferation through inhibition of the Receptor Activator of NF-κB Ligand (RANKL) pathway. Cell Metabolism (2014, in revision). Mentor: Robert Yanagisawa, M.D. Phone: 212-241-3367 E-mail: [email protected] Clinical Research in Bariatric Surgery and Diabetes This is a collaborative study between Dept of Surgery and Dept of Medicine at the Mount Sinai School of Medicine. We have a long history of cohesive working relationship as multidisciplinary Bariatric specialists working together as an American Society for Metabolic and Bariatric Surgery (ASMBS) Center of Excellence. We hope to find the mechanisms leading to early and durable post surgical diabetes resolution with BPD-DS, which appears to be the most effective procedure on diabetes. Randomized study between Sleeve and BPD-DS (Sleeve + duodenal exclusion) has not been done to date and it will provide new insights to insulin secretion and insulin action as it relates to incretin effect. Sleeve and Duodenal Switch Diabetes Study This is a pilot study comparing the mechanisms of diabetes resolution occurring after LBPD-DS and LSG in a prospective randomized fashion. The results of the study will add important information regarding the mechanisms underlying resolution of diabetes after these two procedures Metabolic Profiling Two measures of insulin secretion and sensitivity will be used, the oral glucose tolerance test (OGTT) and the frequently sampled intravenous glucose tolerance test (fsIVGTT) (29). Measuring glucose and insulin levels from oral and intravenous glucose loads will allow physiologic assessment of the incretin effect (Figure 2), isolated beta cell function, and peripheral glucose metabolism. Drs. Inabnet, LeRoith, Lam, and I are coinvestigators. Fellows would gain understanding of physiology behind various bariatric surgery procedures and will be directly involved in conducting and interpreting metabolic profile testing.