Kokkotou Lab

Kokkotou Laboratory

Dr. Kokkotou's current research involves the role of neuropeptides in mediating bidirectional communications between the brain and peripheral tissues, with emphasis on the gut and the adipose tissue. She is particularly interested in the modulation of these interactions by physical and psychological stressors, dietary factors and the microbiota. As a physician-scientist by training, Dr. Kokkotou in her research has adopted a bench-to-bedside, and often multidisciplinary, approach, using both in vitro and in vivo systems. The latter include a battery of genetically manipulated mouse disease models. Her ultimate career goal is to advance treatment options for diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and obesity, where certain neuropeptides, as Dr. Kokkotou's own research has shown, seem to play a crucial role in their pathogenesis.

A native of Greece, Dr. Kokkotou had completed her MD and PhD degrees at the University of Athens, Greece where she also received further clinical training in Pediatrics. She came to Boston to pursue a doctorate (D.Sc) in Cancer Biology at Harvard. Her post-doctoral fellowship was in Endocrinology, with focus on obesity and diabetes type II at Joslin Diabetes Center. She joined the Division of Gastroenterology at BIDMC in 2003 as an Instructor in Medicine and she was promoted to Assistant Professor in 2006. She devotes 100% of her time in research and teaching. As director of Neuropeptide Research, her goal is to bring together an interdisciplinary team of investigators from within the hospital, and the Harvard Community at large, with related interests that will share ideas, expertise and resources and apply for extramural funding.

Current projects in the Kokkotou Lab include:

"Melanin-Concentrating Hormone (MCH) as a mediator of intestinal inflammation" 

MCH is a hypothalamic neuropeptide with an established role in feeding behavior and energy balance. Despite reports in the literature describing the presence of MCH in the gastrointestinal tract as well as on immune cells, the clinical significance of peripheral MCH has not yet been elucidated. We discovered that MCH and its receptor MCHR1 were several fold upregulated in the intestinal mucosa of patients with Ulcerative Colitis and Crohn's Disease, collectively known as IBD. Most importantly, expression of MCHR1 was significantly higher in patients with more advanced disease. Laser capture microdissection followed by real time RT-PCR analysis demonstrated that colonocytes from IBD biopsies had increased expression of MCHR1 mRNA, compared to colonocytes obtained from controls. These findings point to a proinflammatory role of MCH in IBD pathogenesis. Indeed, TNBS-induced experimental colitis is significantly attenuated in the MCH deficient mice. In the same model of intestinal inflammation, MCH immunoneutralization resulted in similar protective effects. Moreover, we found that activation of MCH receptors in colonocytes triggers proinflammatory signaling pathways and cytokine production. We further pursue this line of investigation by a) Testing novel MCH antagonists as treatments for IBD in mouse models of experimental colitis; b) Assessing the role of MCH in adipose tissue hypertrophy seen in Crohn's disease (creeping fat); c) Evaluating the role of MCH in immune cell activation related to colitis d) Delineating the signaling pathways targeted by MCH in intestinal epithelial cells, macrophages and adipocytes.

The tachykinins, a family of evolutionary conserved short neuropeptides, including substance P (SP), neurokinin A, neurokinin B and endokinins, among others, have diverse effects in nociception, stress adaptation, mood, autonomic reflexes, motility and inflammatory responses. Among the three G-protein coupled receptors for tachykinins that have been described the neurokinin-1 receptor (NK-1R) is the high affinity selective receptor for SP and endokinins. We have recently discovered that treatment of obese mice with CJ-12,255 (CJ), a non-peptidic NK-1R pharmacological antagonist, resulted in significant weight loss due to a reduction in fat, but not in lean mass, and in an improvement of their insulin sensitivity. Moreover, CJ administration reduced food intake, both acutely and over longer periods of time, and inhibited refeeding after an overnight fast. Subsequent studies revealed that NK-1R inhibition reduced food intake and adiposity in leptin deficient, ob/ob mice, indicating that the mechanism(s) involved in such effects are, at least in part, leptin-independent. We are currently characterizing the metabolic phenotype of the NK-1R deficient and the substance P deficient mice, under baseline conditions and upon exposure to a western type of diet. Parameters that we examine overtime in those mice include feeding behavior, weight gain patterns, adiposity, energy expenditure, insulin sensitivity, islet function, development of hepatosteatosis, neuroendocrine responses to fasting and serum cytokine and lipid profiles.