Hassan A. Ali, Ph.D., M.S.M.
My research at the Miami Project to Cure Paralysis focuses on understanding the signaling pathways that regulate axon growth, and identifying components of those pathways that can be targeted with drugs to induce robust axon regeneration. Central nervous system (CNS) neurons lack the ability to regenerate their axons, which substantially hampers functional recovery from CNS injuries. The etiology of the problem is complex and mediated by multiple signaling pathways. This necessitates engaging more than one drug target to achieve clinically significant regeneration. However, identifying just one target is difficult, and finding a single drug that engages multiple targets is even more challenging. My laboratory uses three main strategies for solving this complex problem:
- Phenotypic screening: Phenotypic screening is a powerful technique that combines robotics, automated microscopy, and sophisticated image analysis algorithms. It allows us to test live neurons with thousands of compounds and acquire very detailed information on how each individual chemical affects the behavior of the neurons.
- Target-based screening: Target-based screening is a high throughput technology that makes it possible to test hundreds of gene products (targets) with hundreds of thousands of compounds to efficiently determine how each compound modulates the biochemical activity of each target. One very important group of drug targets is the family of kinases. Kinases control almost every function of the cell, and therefor can be targeted to alter most cellular phenotypes, including axon growth. Another advantage of using kinases is that their similarity makes it possible to target more than one of them with just one molecule.
- Machine learning: Machine learning leverages the tremendous power of high performance computing to identify solutions to problems that are too complex to be solved using explicit mathematics. We phenotypically screen kinase inhibitors with CNS neurons to identify ones that promote axon growth in those cells. Then, we use target-based profiling to determine which kinases each of the compounds inhibits. Finally, we use machine learning to relate the two types of data and identify highly effective drug targets. This in turn allows us to discover or develop compounds that are likely to have high clinical efficacy.
Using these approaches, we have identified several promising drug targets for promoting axon regeneration. We also identified a number of molecules that co-engage multiple targets and strongly promote axon regeneration in animal models of spinal cord injury (SCI). We are developing these molecules into potential therapies for rebuilding damaged neural networks and promoting functional recovery from traumatic SCI.
In addition to my work on CNS regeneration, I’m also interested in cancer drug discovery. Kinases play a central role in cancer, and are therefore an intensely pursued drug target family in oncology. The combinatorial approaches developed by my lab provide an infrastructure for oncology drug discovery and personalized cancer medicine. By directly querying the functional state of cells, our methods complement genomic technologies such as exome sequencing and next generation RNA sequencing, which query the “blueprint” of cells. I collaborate with several oncology groups to discover drugs for a number of cancers including sarcoma, lymphoma, leukemia, and breast cancer.
George William Burke, III, M.D., FACS
I am a transplantsurgeon with a special interest in recurrence of disease after kidney or kidney-pancreas transplantation.
Along with Dr. Alberto Pugliese, I have been involved in studying recurrence of auto-immunity in those patients with type 1 diabetes (T1D) and end-stage renal disease who underwent kidney-pancreas transplantation in thepast. Our intention is to address the diagnosis and prediction of recurrent autoimmunity, a significant clinical problem, and to gain insight into the relationship between autoimmune humoral responses, cellular responses and disease progression in the transplanted allograft through biopsy. The pancreas transplant population provides a unique opportunity to conduct such studies, which are not feasible in patients with type 1 diabetes who do not have a transplant. Our ultimate goal is to contribute to the possible treatment and cure of type 1 diabetes through the application of therapy to T1DR.
Our other major interest is the treatment of children with focal segmental glomerulosclerosis (FSGS) and the problematic recurrence of proteinuria after kidney transplant. Ou group initiated a protocol utilizing one dose of rituximab in addition to the standard induction immunosuppression protocol for pediatric patients with FSGS in order to mitigate against the recurrence of proteinuria after kidney transplantation. Serum was collected before and after transplantation. Biopsies were performed pre and post reperfusion, looking for early changes consistent with podocyte foot process dysregulation. This led to our collaboration with Dr.Alessia Fornoni who demonstrated the favorable effect of rituximab clinically was associated with rituximab binding a novel target (SMPDL3B,a sphingomyelinase) on the podocyte membrane. This work has led to further collaborations with Dr. Peter Mundel in which we used abatacept as rescue therapy for patients with recurring proteinuria after kidney transplantation for FSGS in the context of podocyte B7-l expression.Our collaborative work has the potential to shed light on the function of the podocyte, including its role in innate immunity following transplantation, which perhaps may translate into the treatment of primary disease.
These two areas of research represent robust examples of “bedside to bench and back again’‘ translational research.
Gabriel Contreras, M.D., MPH
I earned my medical degree in 1987 from the Autonomous University of Guadalajara in Mexico. I trained in Internal medicine, nephrology, hypertension, critical care, and earned a degree as Master in Public Health between 1989 and 2003. Subsequently, I joined the School of Medicine at the University of Miami. During my time as faculty in the Department of Medicine, I have been involved in the development and establishment of a successful clinical research program in the Division of Nephrology with the accrual of 21 research grants, 68 publications in peer review Journals, and 5 Chapters publications in textbooks. In the 18 years of my academic career, I have kept research funding from different sources such as the Kidney Foundation of South Florida, the Veterans Affairs Cooperative Study Program, the National Institute of Health (NIH) and the Pharmaceutical Industry. I have an ongoing commitment to improving kidney disease outcomes among racial and ethnic minorities throughout the clinical research program at the University of Miami Miller School of medicine. This is evidenced in part by funding for the University of Miami as a key site in the African American Study of Kidney Disease and Hypertension (AASK) trial-cohort, a multi-center, NIH-funded study of risk factors for the prevention and treatment of kidney disease progression among African Americans. I have ongoing funding also as a site Principal Investigator at University of Miami for the Systolic Blood Pressure Intervention Trial (SPRINT) which is sponsored by the National Institutes of Health (NHLBI, NIDDK, NIA and NINDS) throughout Wake Forest University. This is a multicenter clinical trial study exploring the effect of intensive systolic blood pressure control on the risk for cardiovascular and renal diseases. Along with that important work, I have been also engaged in a number of internationally recognized clinical trials of novel treatments for lupus nephritis in racially and ethnically diverse populations. I have ongoing funding as a site Principal Investigator at University of Miami for Randomized, Double-Blind, Controlled, Phase II Multicenter Trial of CTLA4Ig (Abatacept) Plus Cyclophosphamide vs. Cyclophosphamide Alone in the Treatment of Lupus Nephritis. Study funded by National Institutes of Health – NIAID through The University of California. These trials are considered milestone studies that are improving the care of patients.
Yelena Drexler, M.D.
Dr. Drexler’s clinical and research interests include glomerular diseases and resistant hypertension. She is involved in translational and clinical research exploring potential novel treatments for glomerular diseases, particularly focal segmental glomerulosclerosis (FSGS) and IgA nephropathy. She he has co-authored several articles on the identification and treatment of resistant hypertension and the role of mineralocorticoid receptor blockade in patients with chronic kidney disease.
Dr. Drexler obtained her medical degree from the Columbia University College of Physicians and Surgeons. She went on to complete her residency training in Internal Medicine and fellowship training in Nephrology at NewYork-Presbyterian/Columbia University Medical Center. She is board certified in Internal Medicine and Nephrology and has been certified as a Clinical Hypertension Specialist by the American Society of Hypertension.
Tali Elfassy, Ph.D.
Dr. Tali Elfassy is an epidemiologist by training and Assistant Professor in the Department of Medicine, Katz Family Division of Nephrology and Hypertension at the University of Miami Miller School of Medicine. Dr. Elfassy’s research is focused on the area of cardiovascular disease, specifically hypertension, and minority health. In her work, she aims to understanding how complex cardiovascular disease risk factors shape health disparities among minority populations and ultimately inform prevention strategies
Dr. Elfassy’s background is multi-disciplinary. She received her MSPH from George Washington University, after which she worked as a Research Associate for Pfizer and then as a Research Scientist for the New York City Department of Health and Mental Hygiene. It was at the New York City Health Department where she gained an interest in population health and broad based strategies to reduce sodium intake on a population level. Following her experience at the health department, Dr. Elfassy went on to complete her PhD in Epidemiology at the University of Miami where she also conducted her American Heart Association post-doctoral fellowship focused on dietary sodium intake and its association with hypertension among US Hispanics. Following her appointment as an assistant professor, Dr. Elfassy was awarded a University of Miami Clinical and Translational Science Institute KL2 award. As part of this project, she described rates of incident hypertension among US Hispanic participants of the Hispanic Community Health Study/Study of Latinos. Her current NIH/NIMHD K01 funding is an extension of this work and examines genetic, social, clinical, and behavioral factors that contribute to observed differences in hypertension among US Hispanics.
Flavia Fontanesi, Ph.D.
I am interested in elucidating the molecular mechanisms governing mitochondrial function and biogenesis. Mitochondria play a pivotal role in the conversion of nutrients-derived energy in form of ATP molecules, through the mitochondria-housed pathways of Krebs cycle, beta-oxidation, respiration and oxidative phosphorylation (OXPHOS). The overarching long-term goal of my research is to gain a complete understanding of the biogenesis and function of the mitochondrial OXPHOS system. The understanding of the pathways shaping the mitochondrial respiratory chain remains a central and basic issue in the field of mitochondrial biogenesis and bioenergetics and unquestionably one that carries profound biomedical implications. Indeed, perturbations of mitochondrial metabolism have been linked to diabetes and diabetic complications, including diabetic nephropathy. Currently, I am participating in a study aiming to dissect the role of mitochondrial dysfunction in podocyte injury associated with defect in the cholesterol transporter ABCA1.
My interest in cellular respiratory metabolism started early during my undergraduate and graduate studies, where I characterized the mitochondrial dysfunction associated with ophthalmoplegia. After obtaining my Ph.D. I moved to the University of Miami, where I initially focused my work on the assembly process of cytochrome c oxidase, the last enzyme of the mitochondrial respiratory chain, in yeast and mammalian cell cultures. Furthermore, in the last 10 years, I have extensively worked on the characterization of the factors and molecular mechanisms involved in the regulation of mitochondrial gene expression. This process is essential to mitochondrial biogenesis and function because mitochondria are organelles of endosymbiotic origin, which conserve their own genome and gene expression machinery.
Moreover, I am especially interested in the molecular mechanisms interconnecting the assembly of the different components of the OXPHOS system and in particular the pathways involved in mitochondrial supercomplex biogenesis. Mitochondrial respiratory supercomplexes are macrostructures formed by the dynamic association of two or more individual respiratory complexes. Their functional significance has gain particular attention in the last few years due to increasing evidence of the pivotal role these structures play in cellular fitness in health and disease.
Alessia Fornoni, M.D., Ph.D.
- Biology of the podocyte
- Biology of pancreatic beta cells in diabetes
- Personalized Nephrology
- Therapeutic strategies for diabetes and chronic kidney diseases
- Experimental Therapeutics
Our research stems from the idea that key metabolic pathways linked to insulin resistance may affect the function of podocytes and pancreatic beta cells in diabetes. In order to identify targets for drug development with high probability of success, we utilize a simple approach where clinical observations are the major drive to basic science discovery. Cell culture systems, experimental animals and translational bioassays that utilize patient’s sera are being utilized with the final goal to promote a personalized medicine approach to patients care. Our laboratory was the first one to report an important role of sphingolipids in the modulation of podocyte function in focal segmental glomerulosclerosis (Science TM, June 2011) and of cellular cholesterol as a primary determinant of podocyte function in diabetic nephropathy (Diabetes, 2013). Dr. Fornoni works in close collaboration with Dr. George Burke III (Director of Pancreas and Kidney Transplant at the University of Miami) to run an NIH sponsored clinical trial for the use of Rituximab to prevent post-transplant recurrence of proteinuria in patients with focal and segmental glomerulosclerosis (FSGS).
Office and Laboratories
Keywords and Phrases
- Personalized medicine
- Stress activated protein kinases and insulin resistance in diabetes
- Slit diaphragm proteins in pancreatic beta cell function
- Podocytes biology in diabetes
- Podocyte dysfunction in recurrent focal segmental glomerulosclerosis
- Experimental Therapeutics
- Biology of the podocyte
Armando Mendez, Ph.D.
My long term research interests has been in lipid metabolism and lipoprotein abnormalities that lead to cardiovascular disease (CAD) and that occur as a consequence of cardiometabolic disorders including diabetes. Our studies initially focused on cellular lipid transport with emphasis on reverse cholesterol transport and the intracellular trafficking of cholesterol from sites of accumulation to sites available for removal (efflux) by high density lipoproteins (HDL) and other extracellular acceptors. My laboratory continues to study the role of HDL in promoting lipid efflux and other HDL functions as potential contributors to and biomarkers of CAD risk and prediction. Ongoing research studies atherosclerosis in mouse and rabbit models of disease with studies aimed to elucidate mechanisms by which psycho/social stress accelerates disease progression. Other ongoing studies include evaluating metabolic regulation in the context of obesity and adipose tissue inflammation and evaluating anti-inflammatory drugs and compounds in preclinical models of diabetes and obesity. These latter studies are aimed at identifying novel therapies that may improve glycemic control, modulate systemic inflammation and ameliorate the CAD comorbidities associated with diabetes.
I also have a long term interest in human biomarkers as predictors of disease in both cross-sectional and longitudinal studies with emphasis on cardiovascular diseases and diabetes. I am or have been involved is several large clinical research projects including the Hispanic Community Health Study, The National Children’s Study, the Pediatric HIV/AIDS Cohort Study (PHACS). In collaborations with my clinical colleagues, and following a broader team science approach, I have participated in multiple studies aimed at identifying associations of CAD and lipid-lipoprotein and other biomarker risk factors with a variety of disease states including diabetes and obesity, renal dysfunction, psycho-social stress and human immunodeficiency virus infection, and spinal cord injury. I am also the Director of the Diabetes Research Institute Biomarker and Immunoassay Core Laboratory that conducts testing related to various aspects of metabolism and endocrinology including diabetes, dyslipidemia, obesity and inflammation. The core lab has allowed me to interact with researchers in many fields of investigation and these interactions have resulted in several long term collaborations in which my role has been to bridge clinical observations and patient specimens with laboratory analysis and mechanistic investigations.
- Garcia-Contreras M, Shah SH, Tamayo A, Robbins PD, Golberg RB, Mendez AJ, Ricordi C. Plasma-derived exosome characterization reveals a distinct microRNA signature in long duration Type 1 diabetes. Sci Rep. 2017 Jul 20;7(1):5998.
- Frej C, Mendez AJ, Ruiz M, Castillo M, Hughes TA, Dahlbäck B, Goldberg RB. A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated With Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex. Arterioscler Thromb Vasc Biol. 2017 37(6):1194-1205
- Bigford GE, Mendez AJ, Betancourt L, Burns-Drecq P, Backus D, Nash MS. A lifestyle intervention program for successfully addressing major cardiometabolic risks in persons with SCI: a three-subject case series. Spinal Cord Ser Cases. 2017 Mar 16;3:17007.
- Szeto A, Sun-Suslow N, Mendez AJ, Hernandez RI, Wagner KV, McCabe PM. Regulation of the Macrophage Oxytocin Receptor in Response to Inflammation. Am J Physiol Endocrinol Metab. 2017;312(3):E183-E189:
- Squitti R, Mendez AJ, Simonelli I, Ricordi C. Diabetes and Alzheimer’s Disease: Can Elevated Free Copper Predict the Risk of the Disease? J Alzheimers Dis. 2017;56(3):1055-1064.
- Noller CM, Mendez AJ, Szeto A, Boulina M, Llabre MM, Zaias J, Schneiderman N, McCabe PM. Structural Remodeling of Sympathetic Innervation in Atherosclerotic Blood Vessels: Role of Atherosclerotic Disease Progression and Chronic Social Stress. Psychosom Med. 2017 Jan;79(1):59-70.
- Garcia-Contreras M, Shah SH, Tamayo A, Robbins PD, Golberg RB, Mendez AJ, Ricordi C. Plasma-derived exosome characterization reveals a distinct microRNA signature in long duration Type 1 diabetes. Sci Rep. 2017 Jul 20;7(1):5998.
Sandra Merscher, Ph.D.
Using a basic science and translational research approach, my laboratory is focused on elucidating and understanding the molecular mechanisms that contribute to the development of proteinuria with a focus on focal segmental glomerulorsclerosis (FSGS) and diabetic kidney disease (DKD).
One area of our research focuses on investigating a novel mechanism by which rituximab, an antibody that has been developed to target B-lymphocytes for the cure of lymphoma, may directly protect podocytes in focal segmental glomerulosclerosis (FSGS). In this study, we are determining if rituximab treatment administered to high-risk patients at time of transplantation protects from recurrent FSGS. Kidney biopsies and a cell-based assay in which human podocytes are cultured in the presence of sera from patients with FSGS are used to determine if rituximab directly protects from podocyte injury through a novel pathway (Science TM, 2011). Our research in this area may lead to a novel clinical indication for rituximab, it may unveil novel targets for antiproteinuric drug development, and may lead to the development of an assay for the pre-transplant identifications of patients at risk for recurrent disease.
The second area of our research focuses on investigating the role of cholesterol accumulation in DKD. We previously described that decreased expression of ABCA1 in podocytes is associated with cholesterol accumulation and apoptosis (Diabetes, 2013). We are investigating the mechanisms leading to decreased expression of ABCA1, cholesterol accumulation, podocyte malfunction, proteinuria and DKD progression using a combination of in vitro and in vivo approaches. Established mouse models for T2D are furthermore used to investigate the potential of Cyclodextrin as a drug to prevent proteinuria and podocytopenia in DKD.
Leopoldo Raij, M.D., FAHA
I have focused my research and educational efforts in the field of hypertension in relation to its link to atherosclerosis, diabetes and kidney disease. The major focus of my scientific endeavors has been to investigate the mechanisms that participate in vascular and renal injury in hypertension. Despite that a significant amount of my research has dealt with basic mechanisms of disease, the ultimate goal has been the translation of our findings into clinical disease with the purpose to prevent disease or develop new therapeutic approaches. I am a recent recipient of the Irvine Page-Alva Bradley Lifetime Achievement Award in Hypertension, sponsored by American Heart Association’s Council for High Blood Pressure Research, an award given for “outstanding contributions to combating hypertension through research, education, and service “. I am a Co-PI of the Miami Field Center of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). In this capacity I serve as the lead physician on our research team. I was a co-author of the initial SOL design paper and am involved in planning and writing other SOL papers.
As Director of the ongoing Program for International Research Scholars of the International Medicine Institute (IMI), of the University of Miami Miller School of Medicine my goal is to develop active scientific interaction between the IMI and research centers of excellence worldwide and Latin America in particular. This program was also invited to collaborate with the Graduate School of the University of Miami in a program that aims at identifying international collaborations on graduate education with foreign Universities, Governments and national and international health organizations with a Focus on Central and Latin America.
Finally the International Research Scholars Program of the IMI works closely with the clinical activities of the IMI designed at facilitating referrals of patients for second opinion as well as treatment in our Medical Center.
In summary, I am committed to continue my endeavors in basic and clinical research, mentoring students, post-doctoral fellows and junior faculty, from Miami, the US, and Latin America, who are devoted to basic and translational research in my areas of expertise.
Michael J. Ricciardi
As a Ph.D. graduate student in the Laboratory of Dr. David Watkins in the Department of Pathology, my research focuses on the role of monoclonal antibodies (mAbs) and their ability to treat and diagnose a variety of diseases. Over the past decade mAbs have become one of the most researched classes of drugs due to their incredible specificity and tolerability. Recent technological advances in mAb development, including hybridoma technology as well as single cell cloning from memory B-cells and plasmablasts, has had an enormous impact on the development of these drugs. Utilizing this new technology, my mentor and I have recently co-founded companies for both the treatment (MABloc Therapeutics, LLC) and diagnosis (Z-Quick Diagnostics, LLC) of emerging infectious diseases including Zika virus, Dengue virus, and others. Additionally, I have founded MAT Biologics, LLC which has specialized in the acquisition and importation of disease state PBMC, plasma/serum, and tissue samples into the US.
Recently, I have seen the opportunity to apply my knowledge of mAbs in fields others than infectious disease, and I have found Autosomal Dominant Polycystic Kidney Disease (ADPKD) as a tremendous opportunity for the utilization of mAb technology. Currently, there are very few treatment options. Moreover, existing options are generally poorly tolerated by patients and have limited effect on the disease after the first year. This inspired me to begin researching this disease in greater detail and co-founding another company, Liberty Biotech, LLC, where we have filed a patent for a mAb to target cystic cells in the kidneys of ADPKD patients. We hope to continue into animal models and partner with drug developers in the future to deliver site specific therapy.
Lina Shehadeh, Ph.D.
Dr. Shehadeh’s laboratory is investigating the molecular mechanisms by which microRNAs regulate atherogenesis and stem cell differentiation. In parallel with the mechanistic studies, the Shehadeh lab is actively engaged in developing a targeted delivery method for microRNAs using aptamer technology. Dr. Shehadeh’s expertise in computational biology and data mining allows her to compile masses of genomic datasets to identify candidate genes and microRNAs with potential therapeutic functions. Her research has identified Osteopontin as a major regulator of heart failure and Alport pathology. In addition to animal models, she uses translational tools such as AAV9 gene therapy, RNA aptamers, and monoclonal antibodies to reverse heart failure and prevent cholesterol influx in renal tubules.
Ivonne Hernandez Schulman, M.D.
High blood pressure is a leading cause of cardiovascular disease, including heart attack, heart failure, stroke, and kidney disease, in the United States. Dr. Ivonne Schulman is a high blood pressure and kidney disease specialist with expertise in how circulating factors and aging affect blood vessel and cardiovascular function. Dr. Schulman’s research focuses on identifying the mechanisms underlying the cardiovascular regenerative capacity of stem cells. In particular, her studies investigate the effect of circulating factors and aging on stem cell growth and differentiation, as it relates to cardiovascular health, using the tools of cell and molecular biology, biochemistry, microscopy, and small animal models.
In light of the growing number of elderly in the United States population, prevention and treatment of cardiovascular disease, the leading cause of death and disability among the aging population, is of paramount importance. Investigating the function of stem cell populations in the cardiovascular system during aging is both important from a therapeutic potential and developmental understanding. A stem cell must retain capacity to self-renew and differentiate into various cell types to regenerate aged or injured blood vessels as well as heart and kidney tissues and restore normal function. Although drug therapies have been developed to slow the progression of cardiovascular diseases, this approach has significant limitations and does not reverse the disease process, urging the study of additional methods of restoring cardiovascular tissue function. Cell based therapies hold the promise and potential for cardiovascular tissue regeneration and health.
Roberto I. Vazquez-Padron, Ph.D.
NIH-award winning scientist and mentor focused on understanding the cellular and molecular mechanisms underlying vascular obstructive diseases like atherosclerosis, in-stent restenosis, transplant vasculopathy, and arteriovenous fistula failure. Three full-time scientist, two post-doctoral fellows and one graduate students currently form my lab. My laboratory is currently supported by three major NIH grants. I have published +60 peer-review scientific articles and book chapters and presented my work in multiple national and international meetings. I am currently member of NHLBI Mentored Clinical and Basic Science Review Committee and NIH Cardiovascular and Respiratory Sciences (CVRS) Integrated Fellowship Review Group. I was member of American Heart Association’s Vascular Wall Angiogenesis, Atherosclerosis, General and Inflammation Peer Review Committee (2010-2015). I serve as reviewer of multiple indexed journals. In addition to my academic work I am a founder of Miami Cardiovascular Innovations Corp.
Youssef Zeidan, M.D., Ph.D.
My research focuses on the role of sphingolipids in ionizing radiation stress responses. Over the past two decades sphingolipids have evolved as key bioactive lipids in cellular stress responses. Radiation injury induces changes within tumor cells and tumor microenvironment through the sphingolipid second messenger, ceramide. Ceramide can be generated through the de novo or sphingomyelin hydrolysis pathways. Our work in breast cancer cells identified a novel mechanism for regulation of acid sphingomyelinase, a key enzyme in radiation response. One of our major interests is to understand how aberrations in ceramide metabolism contribute to radiation resistance. In particular, various sphingolipid species will be analyzed by mass spectrometry and correlations will be made to enzymatic activities. Both cell culture and mouse models are used. Another focus of the laboratory is to study the contribution of sphingolipid metabolism to radiation–induced normal tissue injury. This is often a challenge that hinders the ability to deliver escalated and potentially curative radiation doses. Finally, a library of ceramide analogues will be tested as potential radiosensitizers or radioprotectants.