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.
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.
Dr. Benveniste is Professor of Anesthesia at Yale and joined the faculty in 2016. Dr. Benveniste’s laboratory is a translational research program and focused on applying preclinical neuroimaging technology including magnetic resonance imaging, positron emission tomography to define biomarkers relevant to neurodegeneration including Alzheimer’s disease (AD), and stroke. Most recently, the focus has been on understanding and visualizing the ‘glymphatic pathway’ which is a newly discovered CSF transport system in the central nervous system involved in brain waste drainage. The glymphatic pathway is dependent on the brain’s state of arousal and different anesthetics produces varying effects on the system’s ability to transport CSF and clear metabolic waste products.
Other research foci in Dr. Benveniste’s laboratory are on: 1) bioenergetics of the developing brain and implications for anesthesia related neurotoxicity and 2) mechanisms of addiction to substances of abuse.
Dr. Benveniste received her MD and PhD in neurobiology from the University Of Copenhagen, Denmark. She completed a post-doctoral fellowship in high field magnetic resonance imaging at the Center for In Vivo Microscopy at Duke University Medical Center in Durham, NC from 1989-1991 after which she completed residency training in anesthesia at the Duke University Medical Center. From there she went onto a faculty position at Duke University from 1996-2001. In 2001 Dr. Benveniste joined the department of Anesthesiology at Stony Book Medical Center as faculty and later as Vice Chair for Research. During this time she set up a preclinical MRI facility at Brookhaven National Laboratory and PET technology was integrated into her work to measure the bioavailability and pharmacokinetics of psychoactive compounds and anesthetic drugs. She move to Yale in 2016 to expanding her research program in understanding how the glymphatic system and cerebrospinal fluid transport is affected in neurodegenerative disease states and aging.
Dr. LaMotte's laboratory investigates the peripheral and central neural mechanisms of pain, itch and touch.
- Experiments on pain examine the functional properties of dorsal root ganglion (DRG) neurons in the rodent. We are currently interested in how electrophysiological and neurochemical changes in these properties, occurring after a chronic compression of the DRG (CCD model), lead to behavioral signs of neuropathic pain.
- Experiments on itch use psychophysical methods in humans to measure the pruritic and nociceptive sensations and altered sensory states produced by the application of pruritic substances to the skin. As part of a collaborative effort with two other laboratories, our psychophysical findings will be compared with electrophysiologically recorded responses of peripheral nerve fibers and of spinothalamic neurons to the same pruritic stimuli.
- Experiments on touch have investigated the peripheral neural coding of object texture, shape and softness.
Dr. Xu’s lab is interested in understanding molecular mechanisms that underlie mammalian aging process; and thus, in the long run, developing therapeutic intervention(s) for aging and age-associated diseases. Currently, our research is focused on:
- To study the impact of epigenetically regulated mechanism on cell and tissue aging. Aging is a major risk factor for many chronic diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. Epigenetics has recently emerged as a possible mechanism controlling gene expression and a potential causative factor for cell/ tissue aging and age-associated abnormalities. Epigenetic regulation is primarily mediated by DNA methylation, posttranslational modify of nucleosomal histones, and non-coding RNAs. To achieve our goal, the cutting-edge technologies such as next-generation sequencing (DNA methyl-seq, RNA-seq, and ChIP-seq), conditional cell/tissue specific transgenic and knock-out mouse models, and phenotype characterization are applied to address our research interest.
- To further investigate the functions and mechanisms of our newly identified longevity genes, Pch-2/TRIP13 and Bmk-1/KIF-11. Testing the hypothesis that loss of function (expression) of certain genes in tissues is a driven force for aging, Dr. Niklason and I examined genome-wide gene expression changes in both age-sensitive cells/tissues and age-resistant cells/tissues of mouse and human. We essentially identified a small number of candidate longevity genes. The C. elegans worm and human cell culture have been employed to test if any of those candidates are indeed having impact on lifespan/health-span regulation.
Paul M. Heerdt
Over the past 25+ years, the vast majority of my research has been within 3 broad categories: a) cardiopulmonary adaptation to the stresses of anesthesia and surgery; b) evaluation of hemodynamic monitoring devices; and c) development of novel neuromuscular blocking drugs. Studies involving cardiopulmonary physiology have been conducted in both the laboratory and clinic, with an emphasis upon a systems biology approach that incorporates functional and molecular aspects of adaptation. Most recently, my laboratory has been incorporating aging and working with analytic approaches for quantifying the efficiency of mechanical coupling between the heart and circulation during acute and chronic pulmonary hypertension. Device evaluations have been largely focused upon methods for monitoring blood flow and tissue perfusion; recent studies have involved experimental models of shock. Our drug development program also involves both laboratory and clinical work, with investigation focused on a novel class of drugs that undergo “molecular inactivation” by the amino acid cysteine. This research has resulted in the design and synthesis of a series of molecules, one of which was recently evaluated for safety and efficacy in a clinical trial.