Basic Science Research

Laura Niklason

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.

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.

Jodi Sherman

The environmental impact of perioperative services is among the largest in all of medicine. Inhaled anesthetics account for 5% of hospital emissions, and 33% of hospital solid waste is generated in the ORs. Anesthesiologists have a unique opportunity and responsibility to improve the pollution profile of our specialty, however little is presently known where to target our efforts. The central goal of Dr. Jodi Sherman research in the Yale University Department of Anesthesiology is to quantify the environmental and public health effects of common drugs and devices for entire anesthetic pathways, so these results may aid in targeted waste reduction and pollution prevention strategies where choices exist, as they often do in clinical practice. Dr. Sherman collaborates with Dr. Julie Zimmerman, Ph.D. and other environmental engineers from the Yale School of Forestry and Environmental Sciences, applying Life Cycle Assessment (LCA) scientific modeling to questions in anesthetic practice, quantifying energy, greenhouse gas emissions, human health impacts, and economic densities of therapeutic drugs, OR devices, and perioperative behaviors to help guide clinical decision making toward more ecologically sustainable practices. Dr. Sherman also serves on the Environmental Task Force of the American Society of Anesthesiologists.

Robert LaMotte

Dr. LaMotte's laboratory investigates the peripheral and central neural mechanisms of pain, itch and touch.

  1. 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.
  2. 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.
  3. Experiments on touch have investigated the peripheral neural coding of object texture, shape and softness.

Xiangru Xu

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:

  1. 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.
  2. 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.