Research and Funding Opportunities

Basic and Translational Science

Pediatric Surgery (Dr. David Stitleman)

Because of recent advances in our ability to analyze genetic information, target and edit cells, fetal therapy research is beginning to examine ways to correct genetic diseases in the unborn patient. The Human Genome Project published the sequencing map of the human genome in 2003. Since then the field has exploded, elucidating genes and their mutations throughout biology. Although many genetic diseases are understood down to the molecular level- Huntington’s Disease, Fredrich’s Ataxia, Tay-Sachs, Cystic Fibrosis, Down’s Syndrome, Muscular Dystrophy, Wilson’s Disease and Sickle Cell Anemia -- cures are elusive.

Gene therapy, correction of genetic diseases by replacement or editing the defect, offers a specific and rational treatment and possible cure. Clinical trials in post-natal human gene therapy have been limited by several factors, including inefficient gene product delivery and host immune reactions against vectors and gene products.

Current projects include the development of in-utero gene therapy, which introduces gene therapy before the development of the immune system. The small size and gestational state of the fetus allows relatively higher doses of vector administration to a subject that has a higher proportion of stem cells.

Preliminary work in mice shows broad, high level expression of reporter genes following in utero injection to several tissues including brain, liver and muscle (up to 100% of cells in some organs). Translating this work in animals to the clinic is technically feasible: fetal surgeons and maternal fetal medicine specialists can already access and cannulate umbilical vessels in utero to administer cellular or gene therapy. In addition, advances in prenatal molecular screening have become sophisticated enough to sequence the whole genome of a human fetus as early as the first trimester from a simple blood test from the mother’s blood (analyzing cell free DNA). If successful, this line of research could revolutionize therapy for genetic diseases.

Yale University, with its strong foundation in molecular biology, biomedical engineering and medicine, allows us a unique and powerful opportunity to advance this line of research.

Pediatric Surgery (Dr. Robert Cowles)

Harboring specific clinical interests in pediatric gastrointestinal and hepatobiliary diseases, Dr. Cowles directs a research laboratory focused on intestinal physiology. Specific interests involve the neural control of intestinal adaptation, neural processes involved in recovery from intestinal injury, and the ability of the Enteric Nervous System (ENS) to regenerate.

The primary focus of the lab includes defining the roles of various enteric neurotransmitters, particularly serotonin (5-HT) and acetylcholine (ACh), on small intestinal mucosal proliferation with the objective to develop new therapies for gastrointestinal malabsorptive disorders, such as short bowel syndrome.

Previous work from this laboratory has established the role of enteric 5-HT as a mucosal growth factor, demonstrating de novo intestinal mucosal growth in mouse models of potentiated 5-HT signaling. More recently, we have been exploring the effects of specific 5-HT receptor agonists on mucosal proliferation, coupled with in vitro studies aimed at delineating the signaling pathways and mechanisms at the cellular and molecular level. Other ongoing projects include studying the protective effects of potentiated 5-HT signaling in intestinal ischemia-reperfusion injury.

Future directions of the lab are aimed at transitioning our previous work in mice to a surgical short bowel model in piglets and defining the role of the small intestinal microbiome in mucosal homeostasis.

The lab is funded by foundation grants and through the section of pediatric surgery and welcomes residents from Yale and other programs throughout the country. Our lab is ideally suited for self-motivated residents interested in pursuing an academic career in pediatric surgery or general surgery. Research Fellows present their work at various national meetings such as ACS, AAP, APSA, and ASC. Each Fellow typically publishes 3-6 first-author original scientific publications as well as review articles, clinical studies, case reports, and book/monograph chapters.

Interested residents and students should contact Dr. Cowles directly at: robert.cowles@yale.edu

Yale Endocrine Neoplasia Laboratory (Dr. Tobias Carling)

The focus of the Carling lab is to investigate the genetic and epigenetic causes of endocrine neoplasia. The lab has conducted extensive research on the molecular pathogenesis of thyroid (Papillary carcinoma, follicular carcinoma, follicular adenoma, anaplastic thyroid carcinoma, & Hurthle cell carcinoma) and adrenal tumors (Pheochromocytoma, adrenocortical adenoma, and adrenocortical carcinoma). We have a well-established research model for comprehensive genetic and epigenetic characterization of endocrine tumors with the aim of developing novel personalized treatment approaches. Results of our research are featured in prominent journals such as Science, PNAS, Cell, Surgery, JAMA Surgery, and Nature Genetics.

To learn more please click here.

Vascular Surgery (Dr. Alan Dardik)

The Dardik laboratory studies the healing and function of blood vessels and synthetic blood vessel substitutes that are used in patients having vascular bypass surgery. We are currently trying to understand the fundamental molecular mechanisms by which vein graft adaptation results in positive remodeling and successful adaptation to the arterial environment, yet often proceeds, in the long-term, to neointimal hyperplasia and graft failure. The laboratory has made the original observation that vein graft adaptation is associated with diminished Eph-B4 expression (Kudo et al., ATVB 27:1562, 2007). We are currently investigating the importance of modulating Eph-B4 function in vein graft adaptation, and have recently published that Eph-B4 is active in adult veins, regulates venous remodeling, and that Eph-B4 function depends on receptor phosphorylation and association with caveolin-1 signaling (Muto et al., J Exp Med 208:561, 2011).

The laboratory is funded from the NIH, the VA, as well as from the Yale Department of Surgery Ohse award. As part of Yale's Vascular Biology and Therapeutics program, the lab is located on the 4th floor of the Amistad building. Members of the Dardik laboratory include surgery residents from Yale and other programs as well as postdoctoral fellows and students from around the world.

To learn more please click here.

Gastroenterology Translational Research Laboratory (Dr. John Geibel)

Dr. Geibel’s laboratory has a focus on translational medicine as the overarching theme for the research that is conducted. For studies involving animal work there are two main species that are used, the rat and the mouse.

Intestinal Transport
Under this theme the lab investigates issues associated with water and electrolyte transport in health and disease, such diverse themes from secretory diarrhea to microbiome to ischemic injury are studied in the ileum, and colon both at the cellular level, and in isolated intestinal loop. In this area we are also investigating alternative organ preservation solutions in collaboration with the transplant section.

Gastric Ion Secretion
This theme is associated with modulating levels of acid production in isolated gastric glands from animal and human models. We investigate alternative ways to prevent secretion, and further try to determine the reasons for the hypersecretion of acid and look for means to reduce or prevent this overproduction. Recently we have developed a series of natural products to prevent the secretion of acid that are fast acting and prevent secretion for extended times without the side effects of a PPI.

Renal Ion Transport
In this area we use isolated perfused renal tubules to investigate the production of renal stone disease and determine if activation of the Calcium Sensing Receptor can prevent recurrence of stone disease and also modulate calcium absorption.

3D Bioprinting
The newest theme and perhaps the most exciting is the development of 3D printed tissues and organs using a Bioprinting technology. This technology allows for the rapid development of a replacement tissue using the printer. We are focusing our efforts on arteries and veins, intestine, and eventually liver. In a close collaboration with the leading commercial company that makes bioprinters; it is hoped that we will accelerate the actual printing time further and not be limited by the size of the print we wish to make. To date we have already begun to implant some of the printed vessels into rats in a collaboration with the Dardik laboratory.

Cardiac and Vascular Biology and Immunology (Dr. George Tellides)

Dr. Tellides has an interdisciplinary, translational approach to vascular biology and immunology. Our primary research interest is in conduit artery remodeling. Studies of immune-mediated vascular disease are performed using clinical specimens, cultured human tissues and cells, small animal models, and cellular and molecular techniques.