Basic Science Research

Laura Niklason

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Dr. Niklason is a Professor at Yale University in Biomedical Engineering and Anesthesia, where she has been on faculty since 2006. Dr. Niklason’s research focuses primarily on regenerative strategies for cardiovascular and lung tissues, and the impact of biomechanical and biochemical signals of tissue differentiation and development. For her work in creating engineered arteries, Niklason was named one of only 19 “Innovators for the Next Century” by US News and World Report in 2001. Niklason’s lab was also one of the first to describe the engineering of whole lung tissue that could exchange gas in vivo, and this work was cited in 2010 as one of the top 50 most important inventions of the year by Time Magazine. She was inducted into the National Academy of Inventors in 2014.

Niklason received her PhD in Biophysics from the University of Chicago, and her MD from the University of Michigan. She completed her residency training in anesthesia and intensive care unit medicine at the Massachusetts General Hospital in Boston, and completed post-doctoral scientific training at Massachusetts Institute of Technology. From there she went onto a faculty position at Duke University, where she remained from 1998-2005, before moving to Yale.


Dr. Niklason’s laboratory is focused on cellular therapies, for the cardiovascular system and for the airways/lungs.  Dr. Niklason has a secondary appointment in Biomedical Engineering, and runs an NIH-funded laboratory that focused on using cells as building blocks for therapeutics.  Engineered blood vessels are cultured in vitro from vascular smooth muscle and endothelial cells, inside of bioreactors that apply pulsatile strain to the growing tissues.  To render the resultant engineered arteries non-immunogenic, the vessels are decellularized at the end of culture, thereby producing an engineered vascular extracellular matrix tube that functions as an artery when implanted in vivo.  These vessels have progressed to Phase III clinical trials.  On the pulmonary front, Niklason is working both on culturing engineered tracheas in vivo, and also on prototypes for regenerated whole lungs that are capable of gas exchange.  Engineered tracheas that are grown in bioreactors using cells and non-degradable stenting materials have been tested in rodents and primates, and are functional to several months.  Engineered lungs are cultured on decellularzed native lung scaffolds, and possess some of the mechanical and physiological properties of native organs.  Niklason’s laboratory currently numbers about 12 people, at the undergraduate, graduate, and post-graduate levels.

Time Magazine 50 Best Inventions of 2010 for Engineered Lung, 2010.

Cardiovascular regenerative medicine has taken many avenues over the past three decades. One approach currently in clinical trials does not require any cells from the patient, and is an engineered tissue that is available "off-the-shelf". Our approach to vascular engineering involves seeding allogeneic vascular cells onto a degradable substrate to culture vascular tissues in a biomimetic bioreactor. After a period of 8-10 weeks, engineered tissues are then decellularized to produce an engineered extracellular matrix-based graft. The advantage of using allogeneic cells for graft production is that no biopsy need be harvested from the patient, and no patient-specific culture time is required. The acellular grafts can be stored for 6 months and are available at time of patient need. These grafts are being tested in 3, Phase I clinical trials in Europe and in the US. These tissue engineered vascular grafts have been tested most extensively as hemodialysis access in patients who are not candidates for autogenous arteriovenous fistula creation, with the first patient being implanted in December 2012 in Poland. Since that time, a total of 60 patients have been implanted with engineered, acellular grafts for dialysis access, 40 patients in Europe and 20 in the US. Patients utilize the grafts for dialysis access as soon as 4-8 weeks after graft implantation. This early experience supports the potential utility of this novel tissue engineered vascular graft to provide vascular access for hemodialysis.

The decellularization approach has also allowed us to generate scaffolds to support whole lung regeneration. Using rat, porcine and human sources of organs, lungs have been subjected to a range of decellularization procedures, with the goal of removing a maximal amount of cellular material while retaining matrix constituents. Next-generation proteomics approaches have shown that gentle decellularization protocols result in near-native retention of key matrix molecules involved in cell adhesion, including proteoglycans and glycoproteins. Repopulation of the acellular lung matrix with mixed populations of neonatal lung epithelial cells results in regio-specific epithelial seeding in correct anatomic locations. Survival and differentiation of lung epithelium is enhanced by culture in a biomimetic bioreactor that is designed to mimic some aspects of the fetal lung environment, including vascular perfusion and liquid ventilation. Current challenges involve the production of a uniformly recellularized scaffold within the vasculature, in order to shield blood elements from the collagenous matrix which can stimulate clot formation. In addition, we have developed methods to quantify barrier function of acellular and repopulated matrix, in order to predict functional gas exchange in vivo.

Helene Benveniste

Helene Benveniste

Biography

Dr. Benveniste is Professor of Anesthesia at Yale. She received her Bachelors degree in Mathematics & Physics from Katedralskolen, Denmark, and went on to the University of Copenhagen, for her MD in 1989 and PhD (Doctor Medicinae) in 1991. As a Research Fellow she trained in high field magnetic resonance imaging (MRI) at Duke University Medical Center with Dr. G. Allen Johnson and developed techniques for brain imaging focused on neurodegenerative disease processes including Alzheimer’s Disease. She then went on to residency in Anesthesiology also at Duke University. Dr. Benveniste joined the faculty in the department of Anesthesiology, Duke University in 1996, where she continued her work in developing diagnostic MRI based platforms for early detection of AD.

In 2001 Dr. Benveniste joined the department of Anesthesiology at Stony Book Medical Center as faculty and set up a preclinical MRI facility at Brookhaven National Laboratory; PET technology was integrated into her work to measure the bioavailability and pharmacokinetics of psychoactive compounds and anesthetic drugs. In 2015, Dr. Benveniste’s laboratory became involved with studies of the ‘glymphatic pathway’ which is a novel peri-vascular based system in the central nervous system involved in brain waste removal. Dr. Benveniste has received national and international recognition for her work. In November of 2016, Benveniste moved to Yale University, where she joined the Department of Anesthesiology and is expanding her research program in understanding how the glymphatic system and cerebrospinal fluid transport is affected in neurodegenerative disease states including aging.

Research

Helene Benveniste's research program focuses on several different topics. Foremost, she and her students, post-docs, and close scientific collaborators are interested in understanding how the brain gets rid of metabolic waste products via the ‘glymphatic system’ (GS). For example, she has developed imaging platforms to examine how cerebrospinal fluid (CSF) circulates in the brain and explored how several critical processes (e.g. vascular pulsatility, type of anesthesia, body position) impact waste removal across the adult lifespan. Furthermore, she has identified substantial differences in waste processing via CSF transport when the brain is exposed to lighter sedation versus deeper anesthetic states and is currently examining the sources of these differences. Second, Benveniste and her colleague Dr. Hedok Lee (MR physicist) are interested in understanding how defects in the waste clearing processes may be contributing to development of cognitive decline and dementia. To that end, they have conducted (and are in the process of conducting) preclinical experiments in transgenic rodent models of small vessel disease (vascular dementia) as well as Alzheimer’s disease. In recent studies they have discovered that the waste clearing processes appear to become defect before brain tissue loss is evident potentially reflecting the importance of the GS system as a therapeutic target in maintaining brain health across the lifespan.

Benveniste and her research group are also interested in understanding how different states of arousal (anesthesia) or mechanical stimulation using may be used to enhance waste clearance and thereby prevent or delay cognitive decline. In collaboration with Dr. Spencer Brinker (Mechanical Engineer) they are now exploring how low intensity ultrasound stimulation (LITUS) may be used to accelerate solute transport through the brain in different states of arousal. They are examining these issues by developing novel LITUS stimulation paradigms and are examining their effect in controlled laboratory environments.

Benveniste and her colleagues’ research receives support from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Leducq Foundation and the Department of Defense office of the Congressionally Directed Medical Research Programs (CDMRP).

Model of the brain’s glymphatic system (From Benveniste et al., Glymphatic System Function in Relation to Anesthesia and Sleep States. Anesth Analg 2019; 128:747-758).

Paul M. Heerdt

Paul M. Heerdt 1

Paul M. Heerdt is a Professor of Anesthesiology at Yale University School of Medicine. Dr. Heerdt earned his MD from the University of Tennessee in 1982 followed by a PhD in cardiovascular pharmacology in 1985. He completed his residency in anesthesiology at Massachusetts General Hospital in Boston and then a fellowship in cardiothoracic anesthesia at Washington University in St. Louis, MO.

Following clinical training, Dr. Heerdt remained on the faculty at Washington University for several years before moving to Cornell University in 1992. At Cornell, he was a faculty member in the departments of Anesthesiology and Pharmacology and also maintained an appointment at Memorial Sloan Kettering Center. In 2016 Dr. Heerdt moved to Yale where he has been conducting clinical and basic science research with a particular emphasis on developing collaborative opportunities for residents, fellows, and junior faculty. He serves on several committees within the Yale School of Medicine and lectures in the medical student pharmacology curriculum. Outside of Yale, Dr. Heerdt is active in the Society of Cardiovascular Anesthesiologists and a member of the editorial board for the Journal of Pharmacology and Experimental Therapeutics.

Research Summary

Over the past 30+ years, the majority of my research has been within 3 broad categories: a) development of novel neuromuscular blocking drugs; b) functional and molecular adaptation of the heart and lungs to the stresses of anesthesia and surgery; and c) cardiovascular support devices and hemodynamic monitoring. Most recently this work has expanded into the area of applied hemodynamics with a focus on capturing real-time data streams in the operating room, ICU, or catheterization laboratory and applying analytic models based upon established physiological principles to build an integrated assessment of cardiopulmonary function and reserve. Under the applied hemodynamics umbrella studies include both laboratory-based investigation of novel signals and analysis methods, and clinical research with faculty members from Anesthesiology, Cardiology, Pulmonology, and Surgery.

Research funding and salary support have been provided by multiple foundations, industry sponsors, the Society of Cardiovascular Anesthesiologists, the American Heart Association, and the National Institutes of Health.

RVP

Robert LaMotte

Dr. LaMotte's laboratory investigates the neural mechanisms of pain and itch.

 We use psychophysical methods in humans to measure the pruritic and nociceptive sensations and altered sensory states produced by the application of pruritic and nociceptive stimuli to the skin. As part of a collaborative effort with another laboratory, our psychophysical findings are compared with electrophysiologically recorded responses of peripheral nerve fibers in primate to the same pruritic and nociceptive stimuli. A major goal is to identify peripheral neural coding mechanisms that could be selectively targeted by novel analgesic or anti-pruritic therapies.


Miriam Treggiari

Dr. Treggiari joins us from the Oregon Health and Science University where she served as Professor and Vice Chair for Research.  She is an internationally recognized leader in the area of clinical and outcomes research in the perioperative setting with special emphasis in critically ill and neurocritical care patients.  She will be joining the Division of Neuro-anesthesia.  She has distinguished herself as an exemplary mentor for faculty and trainees. 

Dr. Treggiari received her medical training in Italy and Switzerland.  Following her residency at Civico Hospital in Switzerland, she completed a fellowship in Critical Care Medicine at the Geneva University Hospital in Switzerland.  She earned an MPH in epidemiology at the University of Washington School of Public Health and Community Medicine.  In 2007, she completed a PhD in Epidemiology at the University of Washington. 

As a researcher, she has successfully developed and implemented numerous interdepartmental and inter-institutional research collaborations.  This is evident by her impressive and sustained record of peer reviewed finding.  Dr. Treggiari’ s research interests have been focused in the areas of clinical and outcomes research in the Perioperative setting with special emphasis in critically ill and neurocritical care patients.  Ultimately, she strives to investigate optimal approaches to patient care with the goal of improving quality of care and patient outcome, as well as protect pts from therapies that are not beneficial.  Her research has focused primarily on critical care topics, ranging from nitric oxide, sepsis, sedation, acute lung injury and subarachnoid hemorrhage.  The majority of her ideas originate from clinical problems and gaps in knowledge encountered at the patient bedside.  Her approach has been to start with a systematic investigation of problem with study designs ranging from meta-analysis to the planning of clinical trials to generate support for evidence-based recommendations.  Her expertise in epidemiology is a great asset during all phases of her research activities from the planning, design, analysis, interpretation and writing of our work. 

Philip Effraim

Dr Effraim is an Assistant Professor of Anesthesiology at Yale University. His research interests are focused on investigating mechanisms of pain and finding novel ways to treat pain. Current studies are focused on the voltage-gated sodium channel Nav1.7, which is a threshold channel preferentially expressed in peripheral sensory neurons and is known to play an important role in human pain signaling. Several proteins that interact with Nav1.7 have been identified, and some which are able to modulate the electrophysiological behavior of Nav1.7. Dr Effraim is using biochemical, biophysical and gene-therapy methods, both in vitro and in animal models, to manipulate those accessory proteins to differentially modulate the behavior of Nav1.7, with the ultimate goal of ameliorating the response to painful stimuli.

David Yanez

Dr. Yanez completed his undergraduate and graduate training in statistics at Arizona State University. David joins us from the Oregon Health and Science University where he was Professor.

David’s area of research is focused on biostatistical research in measurement error models, robust inference, distribution free statistical inference, longitudinal data analysis, joint modeling of mean and dispersion parameters, over dispersion, biostatistical consulting and statistical education. He has interest in biomedical research in cardiovascular disease, anesthesia and critical care medicine, drug prevention studies comparative effectiveness research, biomarker evaluation in both observational studies and clinical trials. He is a dedicated educator with a passion for graduate students and in biostatistics/statistics and scientists in the health sciences.

Dr. Yanez’s scholarship has been directed towards his involvement in multidisciplinary, (multicenter clinical studies) evaluating important clinical questions. He has served as co-investigator on numerous peer review trials covering a wide variety of topics, all of which have direct and important patient care implications. He is also talented at applying his biostatistical expertise across several clinical disciplines