Purpose:
The overall objectives of this program are to provide support for the purposes of testing innovative hypotheses which may have significant impact on digestive diseases research. Our hope is that the investigator can then develop enough preliminary data sufficient for funding of a research grant application by conventional mechanisms (e.g. R01). This program hopes to encourage young investigators and more established investigators in other field to approach problems which are relevant to our understanding of normal intestinal, liver and pancreatic function and to digestive diseases. We are particularly interested in projects that address issues in mucosal immunity, epithelial injury/repair, microbial interactions with intestinal, hepatic and pancreatic tissues. We would like to encourage efforts addressing intestinal motility and the application of novel genetic models (e.g., C. elegans, Drosphilia, etc) to address questions in GI tract development. Questions concerning the relevance of potential applications should be discussed with Nicholas O. Davidson, MD, Director, P&F program (nod@im.wustl.edu). The primary objective of this program is to identify projects that will:
* Lead to further extramural, preferably NIH-funded, research support
* Utilize one of the four Core facilities
Who is Eligible? Full time faculty and senior post-doctoral fellows at Washington University including:
* Junior investigators without independent grant support (excluding career development awards) seeking to establish independence in digestive disease research
* Investigators with independent grant support (past or present) unrelated to digestive diseases-related research, now wishing to enter the field of digestive disease research.
* Investigators with independent grant support who have previously worked in this field but wish to pursue a new research direction in the area of digestive diseases.
IT IS STONGLY SUGGESTED THAT YOU CONTACT DR. DAVIDSON TO DISCUSS ELIGIBILITY AND RELEVANCE PRIOR TO SUBMITTING AN APPLICATION
Application Process:
Click to Download the P&F Announcement/Application Forms: DDRCC Pilot/Feasibility Program Announcement/Applications
Forms are in Adobe Acrobat®
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Reader Application here. 
Current Awardees:
Abstracts of Pilot and Feasibility Projects Awarded for Cycle 8 (05/01/07-04/30/08)
Abstract: The prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including insulin resistance, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Indeed, obesity is tightly linked to the development of hepatic steatosis and the potential progression to non-alcoholic steatohepatitis (NASH). Perturbations in hepatic lipid homeostasis caused by fatty acid oversupply likely play a primary role in the pathogenesis of NAFLD. One attractive mechanism to alleviate hepatic lipid overload is via enhanced mitochondrial fatty acid oxidation (FAO). We have recently shown that a protein called lipin 1 modulates hepatic fatty acid homeostasis at the level of gene transcription. Lipin 1 activates the expression of genes encoding mitochondrial FAO and oxidative phosphorylation (OXPHOS) enzymes via interactions with the peroxisome proliferator-activated receptor (PPARα), a nuclear receptor transcription factor, and its coactivator protein (PGC-α). Our recently-published work suggests that lipin 1 may serve to match rates of FAO with FA supply to maintain hepatic lipid balance. We hypothesize that robust activation of the hepatic lipin 1 system and resulting changes in FAO and OXPHOS enzymes will prevent HF diet-induced hepatic steatosis in mice. This proposal is designed to test our hypothesis.
The pathogenesis of infectious diseases caused by diverse Gram-negative bacteria relies on the surface presentation of virulence proteins. Many of these determinants require the assembly of specialized secretion systems to facilitate their maturation on the bacterial surface. Our previous work with uropathogenic E. coli has identified a key periplasmic chaperone-isomerase, termed SurA, that supports the pathogenesis of cystitis. SurA functions as a chaperone for proteins destined for the bacterial outer membrane (OM) and is conserved among many Gram-negative pathogens, including the important human enteric pathogen Salmonella typhimurium. Disruption of surA in Salmonella is associated with attenuated virulence in a murine model of oral infection, but the molecular basis of this defect is unexplored. Salmonella pathogenesis relies primarily on the function of two type III secretion systems (termed SPI-1 and SPI-2), which deliver bacterial effector molecules into host cells through needle-like structures on the bacterial surface. Thus, we hypothesize that maturation of key OM protein components of these Salmonella secretion systems is dependent on the action of SurA or related periplasmic chaperones. The specific aims of this proposal are (1) to determine the effects of surA disruption on the assembly and function of the two Salmonella type III secretion systems, using a mouse model of oral Salmonella infection, whole-mouse bioluminescence imaging, and in vitro type III secretion assays, and (2) to define the spectrum of candidate SurA substrates in Salmonella through a proteomic study of outer membrane fractions in wild-type and surA mutant bacteria. Demonstrating the reliance of type III secretion in Salmonella on SurA function will substantially advance SurA as a bona fide anti-infective target. Identification of such targets and inhibition of critical infectious processes (rather than bacterial killing) is likely to represent a vital strategy in ongoing anti-infective development, as widespread bacterial resistance develops against traditional agents.
Summary: Salmonella is an important cause of bacterial enteritis in humans. In this proposal we will determine how the bacterial protein SurA helps Salmonella to cause disease. We hope to use the information learned to develop new antibiotics that block the activity of the SurA protein.
Abstract: Irritable bowel syndrome (IBS) is a common and morbid functional gastrointestinal disorder of uncertain pathophysiology. Functional MRI (fMRI) brain imaging studies suggest that a combination of central symptom amplification mechanisms and defective pain inhibitory pathways within key cerebral regions of interest (ROls) may be relevant. However, cerebral pain responses exhibit considerable heterogeneity in IBS patients, indicating that the degree of CNS contribution to IBS symptoms is variable. The overarching hypothesis of this protocol is that somatization (Som) is a feature which, when present in IBS patients, is associated with: (I) aberrant cerebral responses to noxious stimuli within ROls as measured by fMRI, and (2) blunted treatment response to standard IBS therapies, including tricyclic antidepressants (TCAs). The specific aims of this study thus will be to measure both the effect of Som on cerebral responses to noxious visceral stimuli in IBS patients, as well as the effect of Som on the persistence of abnormal cerebral pain responses following IBS treatment with TCAs. For the first aim, fMRl studies will be performed in IBS subjects with high degrees of Som (IBS-HDS, N=8), low degrees of Som (IBS-LDS, N=8), and healthy controls (N=8) applying simultaneous visceral stimulation. Som stratification will be accomplished using self-report and interview methods. It is anticipated that IBS-HDS subjects will exhibit higher degrees of ROI activation and greater sensitivity to visceral stimulation compared to IBS-LDS subjects and normal controls. For the second aim, TCA-nalve IBS subjects stratified by Som (IBS-HDS, N=12; IBS-LDS, N=12) will undergo fMRl to assess whether degrees of Som predict improvement in aberrant cerebral pain responses and symptoms in IBS-HDS subjects compared to IBS-LDS subjects following TCA therapy in a placebo-controlled crossover study. The expected outcome is that IBS-HDS subjects will demonstrate attenuated cerebral pain response improvement following TCAs compared to the IBS-LDS group. It is also hypothesized that improvements in bowel symptoms will correlate with normalization of cerebral responses to noxious visceral stimuli. These studies will demonstrate the relationships between Som, cerebral ROI activity, and IBS symptoms. We ultimately hope to identify Som as a set of clinical characteristic that will simplify the recognition of CNS contribution to IBS symptoms, streamlining the targeting of therapeutic inventions.
Abstract: The mammalian intestine epithelium is a physical barrier consisting of a single layer of polarized, terminally differentiated epithelial cells at the luminal surface. The apical cytoplasm of the surface epithelial cells is highly enriched in cytoskeletal elements that are linked to cell-cell junctions. This transcellular network has long been assumed to be critical for maintaining barrier function. However, testing components of this barrier in adult animals is difficult as cytoskeletal genes are typically expressed in many tissues and function in cell division. Vavs, a protein family capable of cytoskeletal regulation show a restricted expression to the surface barrier cells in a limited region of the intestine (the cecum and colon). The surface epithelial cells of mice deficient for all Vavs (Vav1/2/3null) contain an abnormal apical microtubule cytoskeleton that is associated with abnormalities in cell size and polarity. These epithelial defects, in combination with the immune deficiency of Vav1/2/3null mice, predispose to severe mucosal injury of the intestine that mimics features of inflammatory bowel disease. My goals are to define the downstream molecular pathway from Vavs to microtubules in the surface epithelial cells that leads to the stabilization of this cytoskeletal network and to define how the immune system/microbiota participate in the spontaneous bowel injury in a background of defective surface epithelial cells. We hope that these findings will provide new insight and new tools to investigate inflammatory bowel disease in humans.
Abstract: Nonalcoholic fatty liver disease (NAFLD) affects about 20% of adults in the United States. The prevalence of NAFLD is four to five times higher in obese than lean persons and is associated with insulin resistance and the metabolic syndrome. Decreasing calorie intake and increasing physical activity has been recommended as primary therapy for NAFLD, but it is not known whether exercise alone has therapeutic effects on NAFLD. Accordingly, the purpose of this proposal is to determine the effect of endurance exercise without weight loss on: 1) intrahepatic fat content; 2) hepatic lipoprotein kinetics; 3) insulin sensitivity and 4) the cellular mechanisms responsible for the changes observed.
Relevance to Public Health:
Currently, nonalcoholic fatty liver disease (NAFLD) is an important health problem in the US, and it can lead to liver failure in some people. Unfortunately, we do not understand how this disease develops or how to treat it. This study will help us learn more about NAFLD and how to treat it.