Section: Research

Robert Carraway, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Physiology

The Bioactive Neural And Gastro-Intestinal Peptide, Neurotensin (NT)

Research in this laboratory, done in collaboration with Dr. Sazzad Hassan, M.D. (this lab) and Dr. Paul Dobner (Microbiology Dept), is primarily concerned with the neural and endocrine peptide, neurotensin (NT). One focus utilizes radioreceptor assays, bioassays and radioimmunoassays to identify structurally related peptides in the NT-family and to understand their potential roles in signaling. NT pharmacology includes CNS effects (analgesia, neuroleptic, temperature), vascular responses (hypotension, increased vascular permeability), immune system (anaphylaxis, phagocytosis by leukocytes), smooth muscle (contraction of gut, gall bladder, uterus), exocrine secretion (gastric, intestinal, pancreatic), endocrine secretion (pituitary hormones) and effects on cell growth (normal intestinal mucosa, cancer cells).

NT is released from the gut by eating (particularly fat) and one hypothesis under study is that NT functions in concert with CCK to enhance the recycling of bile acids and to promote the digestion and absorption of fatty acids.  Enterohepatic recycling (EHC) of bile acids occurs nearly 10-times/day depending on fat intake, but the regulator is not known. Our recent work shows that physiological levels of NT infused into rats enhance EHC of bile acid taurocholate (TC). Furthermore, the uptake of TC from intestine is inhibited in NT knockout mice and in animals given NT antagonist. The mechanism appears to involve an effect of NT on mast cells which regulate the permeability of the gut. Another hypothesis under study is that NT, released by eating fat, is responsible for the epidemiological association of high fat intake with an increased incidence of certain cancers.  NT-receptors are highly expressed in colon, pancreatic and prostate cancers, and NT has mitogenic activity.  A current study is testing the effects of NT antagonist and NT knockout on growth of prostate cancer cells xenografted in nude mice fed low and high fat chow. 

Signal transduction mechanisms for NT are under study using cultured human prostate cancer cells which exhibit growth responses to NT via the abundantly expressed, G-protein linked, type 1 NT receptor (NTR1).  Experiments are directed towards understanding interactions of NTR1 with other growth regulating systems and our work shows that NT stimulates inositol phosphate metabolism, elevates [Ca²⁺]i by acting on intracellular stores and Ca²⁺-channels, activates PKC, adenylyl cyclase, MAP kinase and lipoxygenase. Recent studies by us indicate that Ca²⁺-channel blockers, lipoxygenase and PKC inhibitors, and general metabolic inhibitors have dramatic effects on NTR1 binding and function, suggesting that these systems feedback to effect receptor functions.  One current hypothesis is that NTR1 is a "sensor" of cellular metabolism and adjusts its mitogenic signaling according to the metabolic status of the cell. 

Specific residues within NTR1 involved in binding and signaling are also being identified by testing the effects of site-specific mutations on the properties of NTR1 expressed in transfected cells (with Dr. Dobner).  These studies may help in identifying the mechanisms involved in feedback regulation, eg., receptor phosphorylation of specific residues may be the basis.

Office: S4-224
Phone: 508-856-2397
E-mail: Robert.Carraway@umassmed.edu
Keywords: Signal Transduction, Cancer, Cell Biology, Animal Models of Disease, Inflammation/Inflammatory Diseases

More on Robert Carraway's Research Research | Figures | Publications | Rotations | Biography | Other View All Sections on One Page