James C. Thompson - US grants

The aim of studies in this proposal is to provide new information regarding the central hypothesis that alterations in metabolism of gut hormones are reflected in changes of gut function. To achieve this end, there are three specific aims. The first specific aim is to study the role of interactions of the immune system and gastrin on ulcerogenesis and carcinogenesis. This aim has three hypotheses: a) that the immune system exerts an inhibitory influence over gastric secretion, b) that in some instances, hypergastrinemia results in a protective action that guards against ulcerogenesis, and c) that hypergastrinemia may facilitate carcinogenesis of the colon. To explore these hypotheses, we plan three general avenues of study: a) to study the role of the immune system in gastric secretion, b) to study possible mechanisms that protect against ulcerogenesis during hypergastrinemia, and c) to study the influence of hypergastrinemia on chemically-induced carcinogenesis of the colon. The second specific aim is to determine the role of gastrointestinal (GI) hormones on pancreatic exocrine and endocrine secretion, pancreatic inflammation, and regeneration of the pancreas in experimental pancreatitis. There are two hypotheses in this aim: a) that pancreatic endocrine and exocrine secretions are normally submaximal because cholecystokinin, secretin and other GI hormones are released and interact at submaximal levels, and b) the secretory status of the pancreas, as influenced by CCK and other GI hormones, influences the prognosis of acute pancreatitis. In order to evaluate these hypotheses, we plan three courses of study: a) to determine the interactions of endogenous CCK and secretin (and related peptide) in vivo and in vitro on pancreatic exocrine and endocrine secretions, b) to study the role of GI hormones in experimental pancreatitis and c) to study the role of GI hormones in pancreatic recovery from pancreatitis. The third specific aim is to determine the role of GI hormones in adaptive hyperplasia of the gut. The hypothesis related to this theme is that hormonal regulation plays a significant role in the mucosal adaptation that follows ileojejunal transposition (IJT) and small bowel resection (SBR). To test this hypothesis, we plan five groups of experiments that are designed to: a) determine the effects of both IJT and SBR on basal and stimulated plasmal levels of neurotensin (NT) and CCK, b) determine the effects of IJT and SBR on mucosal levels of NT and CCK, c) examine steady-state mucosal levels on NT and CCK mRNA after IJT and SBR, d) determine the spatial distribution on NT and CC mRNA and peptide in gut mucosal by in situ hybridization and immunocytochemistry, and e) determine whether increases in steady-state mRNA levels of NT and CCK are associated with changes in rates of transcription. The relation to health of this grant lies in the potential of determining new information regarding firstly, mechanisms of stimulation of acid secretion from the stomach (important in peptic ulcer disease) and in the induction and stimulation of growth of cancer of the gut, secondly, new understanding of the physiology of pancreatic secretion, the role of hormonal stimulation in pancreatitis and factors influencing regeneration after pancreatitis, and thirdly, understanding the role of GI hormones in the hyperplasia of gut mucosa that follows research and transposition (understanding mechanisms of mucosal hyperplasia may provide important information regarding ultimate development of gut cancer).

The long-term objective of this program is to provide new, useful information on the mechanisms by which gastrointestinal hormones (GIH) and related compounds influence body function. We plan to study the synthesis, storage, release, transport, and mechanisms of action of these agents on target cells, target-cell responses, the hormone-hormone interrelationships of these peptides, and their gene expression. In Project 1, we will examine the mechanisms underlying age-related changes in GI hormone metabolism and in responses of the gut and pancreas to trophic stimuli. We will determine the mechanisms by in which age-related changes in GI function may relate to development of disease. In Project 2, we will examine the relevance of chromogranin and its physiologic role in the GI tract and pancreas. We will investigate the action of pancreastatin on the release of insulin from the pancreas. In Project 3, we will examine the effects of GIH hormones on growth of cancers. We will study the mechanisms of trophic actions of GIH. We will determine the role of growth factors in control of growth of GI and pancreatic cancers. In Project 4, we will explore expression of mRNA for parathyroid hormone-related protein and calcitonin gene-related peptide by gut tissues and cells. We will determine the location of the peptides in the gut, identify cellular sites of synthesis and examine the regulation of mRNA expression by the cells. In Project 5, we will define cellular and intracellular mechanisms that mediate effects of steroids on functions of gut and pancreas and on the growth of colonic and pancreatic cancer cells. We will characterize estradiol-binding proteins from various gut and pancreatic tissues. We have established a new Molecular Pathobiology Core to study the effects of trophic gut peptides on expression of cell cycle-related genes and on the expression of autocrine growth factors. Histological localization of neuropeptide gene expression and regulatory mechanisms that affect the level of expression will be examined. Since the last competitive review, we have demonstrated by our publications that our collaboration has been productive; many publications relate to more than one project. With the support of this grant, we have continued to further expand the depth and breadth of our research to meet the long-term objective of this program.

Our long-term objectives are to study the effect of aging on the metabolism and actions of gastrointestinal (GI) hormones. The significance of the proposed research is that, we intend to enlarge upon our observations of age-related changes in gut function, as well as in the mechanisms responsible for these changes, that we have documented during the first phase of studies. These changes may be manifest in the metabolic processes of gut hormones, or in the interaction between GI hormones and their target tissues, at the levels of both the ligand-receptor interface and the post- receptor mechanisms. Clarification of the mechanisms that underlie these age-related changes may contribute to better understanding of the aging process. The specific objectives for this project are: ***1) To study the mechanisms responsible for age-related changes in metabolism of GI hormones and in their action on secretion and motility of the gut. ***2) To study standard models of injury in order to determine the manner in which age- related changes in gut function may be related to development of disease. 3) To explore the mechanisms that are responsible for age-related changes in growth responses of the gut and pancreas to trophic agents. We plan to examine the role of autocrine growth-factors (transforming growth factor {TGF}alpha and beta), polyamine metabolism (including luminal uptake, polyamine content and regulation of enzymes in the polyamine pathway), and protooncogene expression. These studies will address two issues, first, whether there is a breakdown in the normal tight-coupling between cellular proliferation and differentiation in the villus and crypt compartments of the gut, and second, whether these changes predispose to the increased incidence of carcinoma with aging. We will perform similar experiments with the pancreas. 4) To determine whether the prolongation of lifespan achieved by diet-restriction in rodents affects those changes in GI hormone metabolism and mucosal growth of the gut and pancreas that are seen normally with aging. This study will be in collaboration with ongoing studies in San Antonio (Dr. Yu). We anticipate that the studies proposed will allow better understanding of age-related changes in the gut, and we hope that this may lead to improved care for aged patients.

The objectives of this proposal are to investigate the role of gastrointestinal hormones (GIH) in the digestive (and related) processes. We will study the mechanisms for release of neurotensin (NT) from the gut and from medullary carcinoma of the thyroid. We will determine the effect of NT on gastric secretion stimulated by different routes. We plan to characterize cholecystokinin (CCK), NT, bombesin, and peptide YY (PYY) by HPLC. We will determine the differential hepatic uptake of different molecular forms of endogenously released CCK by bioassay and radioimmunoassay. We plan to study the mechanisms of actions of CCK on gallbladder (GB) smooth muscle. We will study the action of PYY on gastric secretion and measure PYY receptors in antrum and fundus. We plan to study the mechanism of relaxation of the sphincter of Oddi by CCK and to determine, by receptor studies, whether substance P is involved. We will determine the relationships between the gut and pancreatic acinus and note particularly the roles of NT, prostaglandins, and indomethacin. We will use whole animals, isolated pancreas, and dispersed acini. We plan to characterize the enterinsulinar relationships of GIH and calcium-regulatory peptides on secretion of insulin and glucagon, to determine whether intracerebroventricular administration of GI and calcium-regulatory peptides influence secretion of insulin and glucagon, and to examine the influence of pregnancy on the relationship between gut hormones and pancreatic endocrine hormone secretion. We will study the role of GIH in the inhibition and stimulation of growth of the pancreas and the relationship with hormone receptors and efficacy of action. We will study the role of stimulatory and inhibitory peptides in the pathogenesis and course of experimental acute pancreatitis. We plan to determine the effects of GIH on the stimulation and inhibition of growth of cancers of the gut and pancreas. We will measure GIH receptors in gut and pancreatic cancer cells. We plan clinical studies on the relationship between GIH and chronic pancreatitis in patients before and after operation. We will continue our metabolic studies on patients with the Zollinger-Ellison syndrome (ZES) and plan to compare nutrition after total gastrectomy in ZES and non-ZES patients. We will study the role of GIH in patients with thryoid disease. We will study the metabolism of NT in man. We will determine the effects of various stages of pregnancy, as compared with the postpartum state, on the relationship between CCK and GB contraction in women.

The Second Galveston International Symposium on gastrointestinal hormones will be held at The University of Texas Medical Branch in Galveston on 2-5 April 1989. The first international symposium on gastrointestinal hormones was held in 1974. It was highly successful. The proceedings was published by The University of Texas Press as a book entitled Gastrointestinal Hormones. It was sold out and was reprinted. This Second International Symposium will address a new, unique and timely topic, namely "Gastrointestinal Endocrinology: Receptors and Post-Receptor Mechanisms". There has been no previous international conference on this topic. We plan to bring together about 100 leaders and young investigators in various disciplines to discuss the newest findings regarding activation of cell receptors by regulatory peptides and the effects of that activation. Young investigators in this field will be specifically invited to participate in this symposium. This symposium is planned to stimulate young and established investigators in sharing current research findings and studies and to promote cooperative efforts in further studies in this rapidly expanding field. The publication of the proceedings will be made so as to disseminate the proceedings of the symposium to scientists and teachers and students in this field. The proceedings will promote the sharing of the deliberations with scientist who could not attend. The conference will begin Sunday evening on 2 April 1989 and will conclude by noon on Wednesday, 5 April 1989. The program will be divided into six major sections: Microbiology and Genetics, Receptors and Post-Receptor Activity, Growth -- Normal and Neoplastic, Physiology of Action of Gastrin and CCK, Clinical Implications, and other major areas. For each section, speakers will present papers pertaining to this topic, and a brief open discussion will be available after each presentation. Speakers chosen by the program committee are scientist of international stature. The number of participants invited will be limited so as to allow effective dialogue and open discussion among the participants. We anticipate that this Second Galveston International Symposium will be as successful as the first and will meet a need for bringing together new information and will further serve as an impetus and foundation for future understanding of the basic mechanisms by which gut peptides exert their regulatory functions over gut physiology.

The long-term objective of this program is to provide new, useful information on the mechanisms by which gastrointestinal hormones (GIH) and related compounds influence body function. We plan to study the synthesis, storage, release, transport, and mechanisms of action of these agents on target cells, target-cell responses, the hormone-hormone interrelationships of these peptides, and their gene expression. In Project 1, we will examine the mechanisms underlying age-related changes in GI hormone metabolism and in responses of the gut and pancreas to trophic stimuli. We will determine the mechanisms by in which age-related changes in GI function may relate to development of disease. In Project 2, we will examine the relevance of chromogranin and its physiologic role in the GI tract and pancreas. We will investigate the action of pancreastatin on the release of insulin from the pancreas. In Project 3, we will examine the effects of GIH hormones on growth of cancers. We will study the mechanisms of trophic actions of GIH. We will determine the role of growth factors in control of growth of GI and pancreatic cancers. In Project 4, we will explore expression of mRNA for parathyroid hormone-related protein and calcitonin gene-related peptide by gut tissues and cells. We will determine the location of the peptides in the gut, identify cellular sites of synthesis and examine the regulation of mRNA expression by the cells. In Project 5, we will define cellular and intracellular mechanisms that mediate effects of steroids on functions of gut and pancreas and on the growth of colonic and pancreatic cancer cells. We will characterize estradiol-binding proteins from various gut and pancreatic tissues. We have established a new Molecular Pathobiology Core to study the effects of trophic gut peptides on expression of cell cycle-related genes and on the expression of autocrine growth factors. Histological localization of neuropeptide gene expression and regulatory mechanisms that affect the level of expression will be examined. Since the last competitive review, we have demonstrated by our publications that our collaboration has been productive; many publications relate to more than one project. With the support of this grant, we have continued to further expand the depth and breadth of our research to meet the long-term objective of this program.

The objectives of this proposal are to investigate the role of gastrointestinal hormones (GIH) in the digestive (and related) processes. We will study the mechanisms for release of neurotensin (NT) from the gut and from medullary carcinoma of the thyroid. We will determine the effect of NT on gastric secretion stimulated by different routes. We plan to characterize cholecystokinin (CCK), NT, bombesin, and peptide YY (PYY) by HPLC. We will determine the differential hepatic uptake of different molecular forms of endogenously released CCK by bioassay and radioimmunoassay. We plan to study the mechanisms of actions of CCK on gallbladder (GB) smooth muscle. We will study the action of PYY on gastric secretion and measure PYY receptors in antrum and fundus. We plan to study the mechanism of relaxation of the sphincter of Oddi by CCK and to determine, by receptor studies, whether substance P is involved. We will determine the relationships between the gut and pancreatic acinus and note particularly the roles of NT, prostaglandins, and indomethacin. We will use whole animals, isolated pancreas, and dispersed acini. We plan to characterize the enterinsulinar relationships of GIH and calcium-regulatory peptides on secretion of insulin and glucagon, to determine whether intracerebroventricular administration of GI and calcium-regulatory peptides influence secretion of insulin and glucagon, and to examine the influence of pregnancy on the relationship between gut hormones and pancreatic endocrine hormone secretion. We will study the role of GIH in the inhibition and stimulation of growth of the pancreas and the relationship with hormone receptors and efficacy of action. We will study the role of stimulatory and inhibitory peptides in the pathogenesis and course of experimental acute pancreatitis. We plan to determine the effects of GIH on the stimulation and inhibition of growth of cancers of the gut and pancreas. We will measure GIH receptors in gut and pancreatic cancer cells. We plan clinical studies on the relationship between GIH and chronic pancreatitis in patients before and after operation. We will continue our metabolic studies on patients with the Zollinger-Ellison syndrome (ZES) and plan to compare nutrition after total gastrectomy in ZES and non-ZES patients. We will study the role of GIH in patients with thryoid disease. We will study the metabolism of NT in man. We will determine the effects of various stages of pregnancy, as compared with the postpartum state, on the relationship between CCK and GB contraction in women.

This award provides support to George Mason University for the acquisition of a high performance 3 Tesla (3T), whole body Magnetic Resonance Imaging (MRI) scanner to support innovative, transformative research into brain and body. The new 3T MRI system, along with sophisticated coils and software, will be the centerpiece of an Interdisciplinary Multimodal Imaging Center (IMIC). MRI allows detailed, noninvasive imaging of brain and body anatomy and connectivity; function via blood oxygen level dependent (BOLD) responses; and metabolism via magnetic resonance spectroscopy. GMU scientists, representing more than eight disciplines across five colleges, will benefit from this award by collaborating to conduct cross-cutting interdisciplinary research on groundbreaking associations between brain and body. The 3T MRI scanner will also enable researchers at GMU to conduct innovative training of undergraduates, graduate students, and junior scientists in brain-body science approaches. This group of researchers all take advantage of our location in the Northern VA/Washington DC region to study sample diverse in age, disability status, ethnicity, and socioeconomic status.

One central theme to the research of GMU investigators is to understand the interrelations of brain and body functions from a biological, psychological, and social perspective, and the alterations of those relationships in the presence of acute and chronic stress, trauma, and pain. Examples of the interdisciplinary research programs that will significantly benefit from this instrumentation include: those examining interactions between brain and peripheral nervous systems following stress and trauma; central and peripheral pain perception; neural, gene, and protein networks and social ties; neurodevelopment and head impacts; and sensorimotor integration and control. These and the other MRI research programs at GMU will be greatly advanced by the acquisition of a Siemens MAGNETOM Prisma 3T scanner, which offers industry-leading gradient performance, parallel imaging capabilities, and a supportive and innovative sequence development community. To address the big data challenges posed by the research outlined in this proposal, a data analytics core will be established, comprised of computer scientists, engineers, and biostaticians, to facilitate data handling and storage, and to develop new techniques for the analysis and integration of MRI and related biological, physiological, and behavioral data.

This MRI award is supported by the Directorate for Social, Behavioral and Economic Sciences (SBE) Division of Behavioral and Cognitive Sciences (BCS), The Directorate for Engineering (ENG) and the ENG Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET).

Abstract (30 lines) Adolescent substance use is a significant public health problem that predicts future substance use disorders in adulthood. Precise understanding of risk factors is needed to develop and target preventions. A large body of research has identified the parenting environment as a strong risk factor for adolescent substance use. However, the brain mechanisms for effects of parenting on substance use are not known. In our current NIDA-funded R01 study, we found that maladaptive parenting behaviors measured in our novel laboratory parent-adolescent interaction task (PAIT) significantly predicted current and future (1 year later) substance use in 245 early adolescents. As a next step, in this R01 renewal application, we propose to team with a neuroscientist (co-PI Thompson) to investigate emotion- and reward-related brain mechanisms of effects of parenting on adolescent substance use. We conducted a pilot fMRI study with 72 of the adolescents from the R01 study and found initial evidence that observed parenting behaviors in the laboratory PAIT task predicted altered fronto-limbic-striatal activation to negative emotion and reward and that these brain responses predicted future adolescent substance use. Further, we found that these brain pathways differed by gender, with girls showing a pathway characterized by heightened fronto-limbic activation to negative emotion and boys showing a pathway characterized by heightened fronto-striatal activation to reward. The proposed renewal study will formally examine gender-differentiated brain pathways from parenting to adolescent substance use in a large sample with a greater range of parenting behavior. We will recruit 326 substance-naive 11-12 year olds and their parents, with 40% oversampled for maladaptive parenting. In a laboratory session, we will measure observed parenting behaviors and adolescent physiological responses in our PAIT task, validated in the current R01 study. Adolescents will complete fMRI sessions to examine brain functional activation (and also functional connectivity) in standardized emotion processing, reward processing, and resting-state tasks which we piloted in the current R01 sample. We will collect detailed behavioral and biological measures of substance use and problem use, emotion and reward sensitivity, and reported parenting at baseline and 1, 2, and 3 year follow-ups into middle adolescence. We will examine: 1. Parenting in PAIT predicting adolescent emotion- and reward-related brain function by gender and 2. Adolescent brain function predicting increases in substance use over three years, by gender. The study will be the first to integrate laboratory assessment of parenting with neuro- imaging to understand brain-based mechanisms of parenting effects on substance use. By identifying brain mechanisms of parenting effects, and gender differences in these, we can better target and strengthen parenting-focused prevention programs and develop gender-sensitive preventions.