Section: Research

Robert Carraway, Ph.D.

  

The Bioactive Neuroendocrine Peptide, Neurotensin (NT)

Research in this laboratory, done in collaboration with Dr. Paul Dobner 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), 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 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. Our work shows that NT infused into rats enhances EHC of bile acid taurocholate (TC) and that the uptake of TC from intestine is inhibited in NT knockout mice. The mechanism appears to involve an effect of NT on mast cells which regulate the permeability of the gut. Another hypothesis 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 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, 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.   

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.  These studies may help in identifying the mechanisms involved in feedback regulation, eg., receptor phosphorylation of specific residues may be the basis.  Zn²⁺ is an important intracellular second messenger which can alter NTR1 binding.  We hypothesize that specific Cys/His residues interact with Zn²⁺ in this regard.

Another recent interest is in developing strategies to target cancer cells by using NT as a homing devise to direct toxic agents specifically to cancer cells that overexpress NTR1.  Toxins that might be coupled to NT include Zn²⁺ ionophores and Zn²⁺ chelators which kill prostate cancer cells by apoptotic or necrotic mechanisms. 

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

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