Medical Student Research Fellowship for Summer 2009

Mentor: Jeffrey Zigman
Department: Internal Medicine/Psychiatry
Room number: Y6.220D
Mail Code: 9077
Phone number: 214-648-6422
E-mail: Jeffrey.zigman@utsouthwestern.edu

Project title #1: Ghrelin and Mood

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 2008-0107

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:
Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight. For instance, ghrelin levels rise in association with hunger and fasting, and ghrelin stimulates food intake and decreases energy expenditure. We recently found that ghrelin levels also rise in association with chronic stress, and that ghrelin has antidepressant actions. Of note, ghrelin is the only known natural peptide that is post-translationally modified by the addition of an n-octanoic acid moiety. The enzyme responsible for ghrelin's unique and critical post-translational modification, GOAT, has only recently been identified, and nothing yet has been published regarding its regulation. Similarly, other important aspects of ghrelin cell physiology remain unknown, such as the cellular machinery involved in ghrelin release, the marked reductions in ghrelin levels observed after Roux-en-Y gastric bypass surgery, and the elevations in circulating ghrelin levels seen after weight loss by dieting and after chronic stress. Also, the identities of other potential modulators of ghrelin secretions and those elements controlling the differential processing of pre-proghrelin into either mature ghrelin or alternate splice products such as obestatin remain elusive. In order to study these processes, we have generated a reporter line in which green fluorescent protein (GFP) is expressed eutopically under the control of the ghrelin promoter. We have recently devised a protocol that allows us to disperse the gastric mucosal cells and subsequently use fluorescence activated cell sorting to gather a highly enriched population of ghrelin cells. We aim to use these cells to study the mRNA content of the ghrelin cells, and the differential regulation of its transcripts under different conditions. Such studies may ultimately reveal important proteins that contribute to ghrelin release and preproghrelin processing. Furthermore, we will pursue methods to study primary cultures of ghrelin cells, using biochemical, electrophysiology and calcium imaging methods to study their responses to various potential ghrelin secretagogues. Finally, we have devised strategies to create immortalized gastric ghrelin cell lines that will serve as novel, readily-available and renewable sources of gastric ghrelin cells with which to screen for ghrelin secretagogues and inhibitors of ghrelin release or ghrelin maturation and with which to study various other facets of ghrelin cell physiology. We are in the process of characterizing these new lines.

Previous Research Activities or Publications with Medical Students:
During the Summer 2008, Mr. Jakub Woloszyn performed research in the Zigman lab as part of a Medical Student Research Fellowship. He had just completed 1st year of medical school at UTSW. His project involved investigating the role of ghrelin in hedonic (pleasurable, rewarding) aspects of eating.

Project title #2: Ghrelin and Mood

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 2008-0107

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:
Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting, and ghrelin stimulates food intake and decreases energy expenditure. We recently found that ghrelin levels also rise in association with chronic stress, and that ghrelin has antidepressant actions. Ghrelin's actions are mediated by interaction with its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Earlier work by our group showed that deletion of GHSR results in altered body weight homeostasis and resistance to diet-induced obesity. Recently, we found that GHSR deletion also alters performance in rodent behavioral tests of depression. We also have found that GHSR has a well-defined, discrete pattern of expression within the brain. This includes co-expression by tyrosine hydroxylase (TH)-expressing dopamine neurons within the ventral tegmental area (VTA), which play an obligatory role in the development of rodent measures of depression. GHSR is also highly expressed within the hippocampus, another site with well established effects on mood. For this project, we will perform a series of studies designed to further explore ghrelin's actions in promoting antidepressant-like behaviors and the mechanisms underlying these actions. We will investigate the effects of chronic ghrelin administration and pharmacologic blockade of ghrelin action on these behaviors. We will also assess the effectiveness of antidepressant agents in mice with blocked ghrelin signaling. Furthermore, we will use our unique ghrelin receptor null mouse model in which ghrelin receptor re-expression can be selectively targeted to either dopaminergic VTA neurons or hippocampal neurons. This selective targeting will involve state-of-the-art neuroanatomical and transgenic techniques, and will help determine if ghrelin action only in dopaminergic VTA neurons or only in hippocampal neurons is sufficient to mediate ghrelin's effects on mood. Finally, we will further explore the mechanism of ghrelin's antidepressant actions by examining the effects of manipulating ghrelin signaling on brain derived nuclear factor (BDNF) action within VTA-NAc circuitry. It is hoped that these studies will result in new therapies to treat mood disorders, and particularly the depression so closely linked to chronic stress and conditions with known perturbations of ghrelin physiology, such as anorexia nervosa and bulimia nervosa.

Previous Research Activities or Publications with Medical Students:
During the Summer 2008, Mr. Jakub Woloszyn performed research in the Zigman lab as part of a Medical Student Research Fellowship. He had just completed 1st year of medical school at UTSW. His project involved investigating the role of ghrelin in hedonic (pleasureable, rewarding) aspects of eating.

Project title #3: Grhelin and Food Reward

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 2008-0107

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)

Brief Description of Project:
Our main research interests revolve around the peptide hormone ghrelin. Ghrelin is produced primarily by endocrine cells lining the stomach and intestine. Since its initial discovery as the endogenous ligand for the growth hormone secretagogue receptor ("ghrelin receptor"), ghrelin has been shown to play an important role in body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting. Also, ghrelin potently stimulates food intake, decreases energy expenditure, and induces obesity when present in high concentrations. Ghrelin's actions are mediated by interaction with its receptor, which has a well-defined pattern of expression within the brain. This includes a high degree of expression in dopamine-containing neurons within a part of the brain known as the ventral tegmental area (VTA). These dopaminergic VTA neurons have been highly studied due to their involvement in brain reward circuits, such as those associated with addiction. The current project includes a series of experiments designed to increase our understanding of the involvement of ghrelin in various hedonic aspects of eating, including reward-seeking behaviors aimed at obtaining diets high in fat the role of the VTA and other brain regions in ghrelin action. To accomplish this, we will subject mice to a battery of tests (including conditioned place preference tests and operant conditioning tests) that will allow us to determine the effect of genetic and pharmacological blockade of ghrelin signaling pathways on food-reinforced reward-seeking behaviors. It is hoped that these studies will result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction.

Previous Research Activities or Publications with Medical Students:

During the Summer 2008, Mr. Jakub Woloszyn performed research in the Zigman lab as part of a Medical Student Research Fellowship. He had just completed 1st year of medical school at UTSW. His project involved investigating the role of ghrelin in hedonic (pleasureable, rewarding) aspects of eating.