I am the director of the Celiac Disease Program at Stanford and I am highly experienced in diagnosis and management of celiac disease and gluten associated disorders.
My objective is to provide excellent and compassionate clinical care for my patients while seeking a better understanding of diseases I treat, particularly Celiac disease (CeD), eosinophilic esophagitis (EoE). My top priorities are patient care and translational research to make new discoveries and improve the care my patients.
- Celiac Disease
- Gluten Sensitivity
- Esophageal Motility Disorders
- Eosinophilic esophagitis
- Eosinophilic Gastrointestinal Disorders
- Gastroesophageal reflux disease
Clinical Associate Professor, Medicine - Gastroenterology & Hepatology
Medical Education: Albert Einstein College of Medicine Office of the Registrar (2002) NY
Residency: Massachusetts General Hospital (2005) MA
Board Certification: Gastroenterology, American Board of Internal Medicine (2009)
Fellowship: Beth Isreal Deaconess Medical Center (2009) MA
Internship: Massachusetts General Hospital (2003) MA
Functional Luminal Imaging Probe (FLIP) Topography Use in Patients With Scleroderma and Trouble Swallowing
FLIP topography has been FDA cleared to evaluate a variety of esophageal conditions, but has never been evaluated in patients with scleroderma. The investigators hope to evaluate this technology in patients who have scleroderma and various esophageal symptoms, and compare to non-scleroderma patients.
Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea.
Digestive diseases and sciences
BACKGROUND: Many anti-nausea treatments are available for chronic gastrointestinal syndromes, but data on efficacy and comparative effectiveness are sparse.AIMS: To conduct a sectional survey study of patients with chronic nausea to assess comparative effectiveness of commonly used anti-nausea treatments.METHODS: Outpatients at a single center presenting for gastroenterology evaluation were asked to rate anti-nausea efficacy on a scale of 0 (no efficacy) to 5 (very effective) of 29 commonly used anti-nausea treatments and provide other information about their symptoms. Additional information was collected from the patients' chart. The primary outcome was to determine which treatments were better or worse than average using a t test. The secondary outcome was to assess differential response by individual patient characteristics using multiple linear regression.RESULTS: One hundred and fifty-three patients completed the survey. The mean efficacy score of all anti-nausea treatments evaluated was 1.73. After adjustment, three treatments had scores statically higher than the mean, including marijuana (2.75, p<0.0001), ondansetron (2.64, p<0.0001), and promethazine (2.46, p<0.0001). Several treatments, including many neuromodulators, complementary and alternative treatments, erythromycin, and diphenhydramine had scores statistically below average. Patients with more severe nausea responded better to marijuana (p=0.036) and diphenhydramine (p<0.001) and less so to metoclopramide (p=0.020). There was otherwise no significant differential response by age, gender, nausea localization, underlying gastrointestinal cause of nausea, and GCSI.CONCLUSIONS: When treating nausea in patients with chronic gastrointestinal syndromes, clinicians may consider trying higher performing treatments first, and forgoing lower performing treatments. Further prospective research is needed, particularly with respect to highly effective treatments.
View details for DOI 10.1007/s10620-020-06195-5
View details for PubMedID 32185665
Clinical and immunomodulatory effects of transcutaneous vagal nerve stimulation for idiopathic gastroparesis
View details for Web of Science ID 000521974900325
RNA-Seq of Gastrointestinal Biopsies During Oral Immunotherapy Reveals Changes in IgA Pathway
MOSBY-ELSEVIER. 2020: AB132
View details for Web of Science ID 000517092700419
Peanut oral immunotherapy induces gastrointestinal eosinophilia in a longitudinal randomized controlled trial
MOSBY-ELSEVIER. 2020: AB84
View details for Web of Science ID 000517092700258
Gastrointestinal Eosinophil Responses in a Longitudinal, Randomized Trial of Peanut Oral Immunotherapy.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time.Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n=15) or placebo (n=5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n=21, 0 weeks), following dose escalation (n=10, 52 weeks), and during the maintenance phase (n=11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis.At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia.In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270.
View details for DOI 10.1016/j.cgh.2020.05.019
View details for PubMedID 32434067
Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy.
2020; 5 (45)
B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE+ B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE+ clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE+ cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE+ and non-IgE-expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE+ B lineage cells in food allergy.
View details for DOI 10.1126/sciimmunol.aay4209
View details for PubMedID 32139586
Open-label pilot study: Non-invasive vagal nerve stimulation improves symptoms and gastric emptying in patients with idiopathic gastroparesis.
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
BACKGROUND: Gastroparesis, a chronic motility disorder characterized by delayed gastric emptying, abdominal pain, nausea, and vomiting, remains largely unexplained. Medical therapy is limited, reflecting the complex physiology of gastric sensorimotor function. Vagus nerve stimulation is an attractive therapeutic modality for gastroparesis, but prior methods required invasive surgery. In this open-label pilot study, we aimed to assess the benefit of non-invasive vagal nerve stimulation in patients with mild to moderate idiopathic gastroparesis.METHODS: Patients self-administered the gammaCore vagal nerve stimulator for 4weeks. The gastroparesis cardinal symptom index daily diary (GCSI-dd) was assessed during a two-week run-in period, ≥4weeks of therapy, and 4weeks after therapy was completed. Gastric emptying and autonomic function testing were also performed. The primary endpoint was an absolute reduction in CGSI-dd of 0.75 after nVNS.RESULTS: There was a total improvement in symptom scores (2.56±0.76 to 1.87±1.05; P=.01), with 6/15 (40%) participants meeting our primary endpoint. Therapy was associated with a reduction in gastric emptying (T1/2 155 vs 129minutes; P=.053, CI -0.4 to 45). Therapy did not correct autonomic function abnormalities, but was associated with modulation of reflex parasympathetic activity.CONCLUSIONS: Short-term non-invasive vagal nerve stimulation led to improved cardinal symptoms and accelerated gastric emptying in a subset of patients with idiopathic gastroparesis. Responders had more severe gastric delay at baseline and clinical improvement correlated with duration of therapy, but not with improvements in gastric emptying. Larger randomized sham-controlled trials of greater duration are needed to confirm the results of this pilot study.
View details for DOI 10.1111/nmo.13769
View details for PubMedID 31802596
Ninety-Six Hour Wireless Esophageal pH Study in Patients with GERD Shows that Restrictive Diet Reduces Esophageal Acid Exposure.
Digestive diseases and sciences
BACKGROUND: Prolonged (96h) pH monitoring may explore the effect of diet on pH and symptoms in patients with GERD.AIMS: To assess the usefulness of a 96h esophageal pH study in patients with GER symptoms under different diets (pro- and anti-GER).METHODS: Prospective study of 66 patients with GERD undergoing wireless 96h pH monitoring. Two-day periods, one on liberal (pro-reflux) and another on restricted (anti-reflux) diet assessed esophageal acid exposure and symptoms. The primary end point was normalization of acid exposure time while on restricted diet. Secondary end point was a>50% reduction in symptoms with restricted diet.RESULTS: Normal (pH time<4 of<6%) was found in 34 patients (51.5%) while on the initial 48h (liberal) diet [median % time<4: 3.2 (95% CI, 1.9, 4.0)] and remained normal while on restricted diet [median % time<4: 2.6 (95% CI, 0.8, 3.4)]. Abnormal acid exposure (% pH time<4:>6%) was found in 32 patients (48.5%) while on initial 48h liberal diet [median % time<4: 10.5, (95% CI 8.9, 12.6)], and decreased significantly with restricted diet [median % time<4: 4.5 (95% CI 3.1, 7.3)] (p=0.001), and normalized with anti-GERD diet in 21 patients (65.6%). Only 11/66 patients were candidates for proton pump inhibitor (PPI) use; 34 had either normal pH studies or normalized them with restricted diet (n=21). Symptoms did not improve with restricted diet.CONCLUSIONS: The 96-h esophageal pH study tests for GERD under pro- and anti-GER diets and allows minimization of PPI therapy to only 16.6% of patients.
View details for DOI 10.1007/s10620-019-05940-9
View details for PubMedID 31734874
- Human Intestinal Enteroids Model MHC-II in the Gut Epithelium FRONTIERS IN IMMUNOLOGY 2019; 10
RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis
2019; 156 (3): 592-+
Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE.We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation.At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection.In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.
View details for DOI 10.1053/j.gastro.2018.10.051
View details for Web of Science ID 000457714300022
View details for PubMedID 30395812
- Esophageal Eosinophilia is Present in Some Peanut Allergic Patients MOSBY-ELSEVIER. 2019: AB310
- An Unexpected Colonic Mass AMERICAN JOURNAL OF GASTROENTEROLOGY 2019; 114 (1): 180–81
- Double Threat: Interplay of Celiac Disease with Inflammatory Bowel Disease. Digestive diseases and sciences 2019
Human Intestinal Enteroids Model MHC-II in the Gut Epithelium.
Frontiers in immunology
2019; 10: 1970
The role of intestinal epithelial cells (IECs) in mucosal tolerance and immunity remains poorly understood. We present a method for inducing MHC class II (MHC-II) in human enteroids, "mini-guts" derived from small intestinal crypt stem cells, and show that the intracellular MHC-II peptide-pathway is intact and functional in IECs. Our approach enables human enteroids to be used for novel in vitro studies into IEC MHC-II regulation and function during health and disease.
View details for DOI 10.3389/fimmu.2019.01970
View details for PubMedID 31481960
View details for PubMedCentralID PMC6710476
- A Positive Correlation Between Gastric and Esophageal Dysmotility Suggests Common Causality DIGESTIVE DISEASES AND SCIENCES 2018; 63 (12): 3417–24
- Baseline Gastrointestinal Eosinophilia Is Common in Oral Immunotherapy Subjects With IgE-Mediated Peanut Allergy FRONTIERS IN IMMUNOLOGY 2018; 9
An Unexpected Colonic Mass.
The American journal of gastroenterology
View details for PubMedID 30333533
- Use of Esophageal pH Monitoring to Minimize Proton-Pump Inhibitor Utilization in Patients with Gastroesophageal Reflux Symptoms DIGESTIVE DISEASES AND SCIENCES 2018; 63 (10): 2673–80
Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems
View details for Web of Science ID 000447268902203
Identification of Risk Factors for Gastric Antral Vascular Ectasia (GAVE) Among Systemic Sclerosis Patients
View details for Web of Science ID 000447268901344
Use of Esophageal pH Monitoring to Minimize Proton-Pump Inhibitor Utilization in Patients with Gastroesophageal Reflux Symptoms.
Digestive diseases and sciences
BACKGROUND: Due to concerns about long-term PPI use in patients with acid reflux, we aimed at minimizing PPI use, either by avoiding initiating therapy, downscaling to other therapies, or introducing endoscopic or surgical options.AIMS: To examine the role of esophageal ambulatory pHmetry in minimizing PPI use in patients with heartburn and acid regurgitation.METHODS: Retrospective cohort analysis of patients with reflux symptoms, who underwent endoscopy, manometry, and ambulatory pHmetry to define the need for PPI. Patients were classified as: (1) never users; (2) partial responders to PPI; (3) users with complete response to PPI. Patients were then managed as: (1) PPI non-users; (2) PPI-initiated, and (3) PPI-continued.RESULTS: Of 286 patients with heartburn and regurgitation, 103 (36%) were found to have normal and 183 (64%) abnormal esophageal acid exposure (AET). In the normal AET group, 44/103 had not been treated and were not initiated on PPI. Of the 59 who had previously received PPI, 52 stopped and 7 continued PPI. Hence, PPI were avoided in 96/103 patients (93%). In the abnormal AET group, 61/183 had not been treated and 38 were initiated on PPI and 23 on other therapies. In the 122 patients previously treated with PPI, 24 were not treated with PPI, but with H2RAs, prokinetics, endoscopic, or surgical therapy. Hence, PPI therapy was avoided in 47/183 patients (26%).CONCLUSIONS: In patients with GER symptoms, esophageal pHmetry may avert PPI use in 50%. In the era of caution regarding PPIs, early testing may provide assurance and justification.
View details for PubMedID 29959725
A Positive Correlation Between Gastric and Esophageal Dysmotility Suggests Common Causality.
Digestive diseases and sciences
BACKGROUND: Gastric and esophageal dysmotility syndromes are some of the most common motility diagnoses, but little is known about their interrelationship.AIMS: The aim of our study was to determine if a correlation exists between gastric and esophageal dysmotility syndromes.METHODS: We reviewed the records of all patients who underwent both solid gastric emptying scintigraphy (GES) and high-resolution esophageal manometry (HRM) withina 2 year period, with both done between August 2012 and August 2017. All GESs were classified as either rapid, normal, or delayed. All HRMs were classified according to the Chicago Classification 3.0. Correlations were assessed using Fisher's exact test and multiple logistic regression.RESULTS: In total, 482 patients met inclusion criteria. Of patients with a normal, delayed, and rapid GES, 53.1, 64.5, and 77.3% had an abnormal HRM, respectively (p<0.05 vs. normal GES). Likewise, patients with an abnormal HRM were more likely to have an abnormal GES (54.9 vs. 41.8%, p=0.005). Multiple logistic regression showed abnormal GES [odds ratio (OR) 2.14], age (OR 1.013), scleroderma (OR 6.29), and dysphagia (OR 2.63) were independent predictors of an abnormal HRM. Likewise, an abnormal HRM (OR 2.11), diabetes (OR 1.85), heart or lung transplantation (OR 2.61), and autonomic dysfunction (OR 2.37) were independent predictors of an abnormal GES.CONCLUSIONS: The correlation between an abnormal GES and HRM argues for common pathogenic mechanisms of these motility disorders, and possibly common future treatment options. Clinicians should have a high index of suspicion for another motility disorder if one is present.
View details for PubMedID 29946871
Baclofen and gastroesophageal reflux disease: seeing the forest through the trees.
Clinical and translational gastroenterology
2018; 9 (3): 137
Baclofen has been shown to decrease reflux events and increase lower esophageal sphincter pressure, yet has never established a clear role in the treatment of gastroesophageal reflux disease (GERD). Lei and colleagues have shown in a recent elegant study that baclofen reduces the frequency and initiation of secondary peristalsis and heightens esophageal sensitivity to capsaicin-mediated stimulation. These findings may help explain both the benefit of baclofen in conditions such as rumination and supragastric belching, as well as the apparent lack of benefit of baclofen and other GABAB agonists in long-term treatment of GERD.
View details for PubMedID 29599487
- Baclofen and gastroesophageal reflux disease: seeing the forest through the trees CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY 2018; 9
Clinical examinations: a medical student's perspective reply
ADVANCES IN MEDICAL EDUCATION AND PRACTICE
2018; 9: 3–4
View details for Web of Science ID 000419108400002
Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems
View details for Web of Science ID 000411824106435
- Outcomes of Endoscopic Procedures on Patients With Left-Ventricular Assist Devices: Experiences From a Single-Center Retrospective Case Series MOSBY-ELSEVIER. 2017: AB207–AB208
Efficacy of Video Capsule Endoscopy in the Management of Suspected Small Bowel Bleeding in Patients With Continuous Flow Left Ventricular Assist Devices.
2017; 10 (5): 280–87
Continuous flow left ventricular assist device (CF-LVAD) patients have a high prevalence of gastrointestinal bleeding from the small bowel. Video capsule endoscopy (VCE) is often used for diagnosis in these patients, but efficacy has yet to be determined. In this study, we evaluated the efficacy of VCE in the management of CF-LVAD patients with suspected small bowel bleeding by comparing to a non-VCE CF-LVAD control group.We retrospectively reviewed the charts of all patients with CF-LVADs implanted at Stanford Hospital from January 2010 to October 2015. Patients were included in the study if there was a clinical suspicion of small bowel bleeding and either a negative upper endoscopy or colonoscopy.A total of 26 patients met inclusion criteria for a total of 15 encounters where VCE was done, and 25 where VCE was not done. There were no statistical differences when comparing these groups in terms of medical therapy use (thalidomide or octreotide), enteroscopy use (double-balloon or push), intervention on lesions, or any 30-day outcomes. There was no advantage to VCE with regard to the composite endpoint time to re-bleed or death related to re-bleeding (median 114 vs. 161 days, P = 0.15) after removing patients who did not get a VCE due to death or critical illness.We did not find VCE changed management or outcomes in CF-LVAD patients with suspected small bowel bleeding at our institution when compared to a non-VCE control group. Our experience is small and single center, and larger, multi-center studies could further elucidate the utility of VCE in this patient population.
View details for PubMedID 29118868
View details for PubMedCentralID PMC5667693
Multi-Organ RNA-Sequencing of Systemic Sclerosis (SSc) Patients Shows Reproducible Gene Expression Profiles Across Organ Systems
View details for Web of Science ID 000417143401207
Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample.
2016; 55 (4): 654-658
Intestinal pseudo-obstruction is a rare gastrointestinal complication in patients with SSc without large studies examining its prevalence or outcomes. We aimed to compare outcomes in SSc patients with intestinal pseudo-obstruction to patients with intestinal pseudo-obstruction secondary to other causes, and SSc patients without intestinal pseudo-obstruction.This is a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the period 2002-2011. We included patients with the previously validated International Classification of Diseases-Clinical Modification-9 code 710.1 for SSc in combination with codes for intestinal pseudo-obstruction, and determined length of hospitalization and the risks for surgical procedures, use of total parenteral nutrition (TPN) and in-hospital mortality.A total of 193 610 SSc hospitalizations occurred in the USA between 2002 and 2011, of which 5.4% (n = 10 386) were associated with a concurrent intestinal pseudo-obstruction diagnosis (cases). In-hospital mortality was 7.3%. In multivariate analyses, cases were more likely to die during the inpatient stay and to receive TPN than patients with idiopathic intestinal pseudo-obstruction (control group 1), patients with intestinal pseudo-obstruction and diabetes (control group 2), and SSc patients without intestinal pseudo-obstruction (control group 3). Cases had longer in-hospital stay than control groups 2 and 3, and were less likely to undergo surgical procedures than control groups 1 and 2.Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality in comparison with other SSc patients and those with intestinal pseudo-obstruction secondary to other causes.
View details for DOI 10.1093/rheumatology/kev393
View details for PubMedID 26615031
- Colonic plasmacytomas: a rare complication of plasma cell leukemia. Endoscopy 2015; 47: E77-8
Intestinal Pseudo-Obstruction in Patients with Systemic Sclerosis: An Analysis of the Nationwide Inpatient Sample.
WILEY-BLACKWELL. 2014: S1310
View details for Web of Science ID 000344384906230
- Dietary gluten triggers concomitant activation of CD4(+) and CD8(+) alpha beta T cells and gamma delta T cells in celiac disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2013; 110 (32): 13073-13078
In silico analysis of T-bet activity in peripheral blood mononuclear cells in patients with inflammatory bowel disease (IBD).
In silico biology
2009; 9 (5-6): 355-363
T-bet (TBX21) is a transcription factor that regulates T-cell differentiation, and has recently been implicated in the pathogenesis of Crohn's disease (CD). The regulatory networks through which T-bet affects immune function are unknown. An NCBI gene expression profile from patients with CD and controls was analyzed. T-bet transcription factor binding sites and promoter modules were identified using promoter analysis software. Functional correlations between T-bet-containing promoters were determined using data mining and ontological analysis. T-bet expression in CD peripheral blood mononuclear cells (PBMCs) (n=59) was significantly reduced compared to control (n=42) (p<0.0001) and ulcerative colitis PBMCs (n=26), (p=0.005). The promoter regions of all genes differentially-expressed in CD were probed for T-bet Transcription Factor Binding Sites (TFBSs). Twenty-three genes contained transcription-factor binding sites for T-bet; 8 were down-regulated, and 15 were up-regulated in CD-PBMCs. Three genes (S100A16, ABHD3 and EZH1) that were down-regulated in CD-PBMCs contained a complex promoter module consisting of T-bet and EGRF transcription-factor binding sites. Ontological analysis revealed that a significant number of differentially-expressed genes that contain T-bet binding sites are involved in innate immunity (8 genes, Z-score 4.11) and signal transduction (5 genes, Z-score 2.65). This combination of gene expression datasets and promoter analysis has identified a network of genes that contain simple T-bet binding sites, and complex T-bet promoter modules, in their promoter regions. These results implicate a mechanism through which T-bet may influence innate immunity in CD.
View details for DOI 10.3233/ISB-2009-0410
View details for PubMedID 22430437
Separable and redundant regulatory determinants in Cactus mediate its dorsal group dependent degradation
2001; 128 (15): 2963-2974
Dorsal-ventral polarity within the Drosophila syncytial blastoderm embryo is determined by the maternally encoded dorsal group signal transduction pathway that regulates nuclear localization of the transcription factor Dorsal. Nuclear uptake of Dorsal, a Rel/NFkappaB homolog, is controlled by the interaction with its cognate IkappaB inhibitor protein Cactus, which is degraded on the ventral side of the embryo in response to dorsal group signaling. Previous studies have suggested that an N-terminally located kinase target motif similar to that found in IkappaB proteins is involved in the spatially controlled degradation of Cactus. We report studies of the in vivo function and distribution of fusion proteins comprising segments of Cactus attached to Escherichia coli beta-galactosidase (lacZ). Full-length Cactus-lacZ expressed in vivo normalizes the ventralized phenotype of embryos that lack Cactus and faithfully reconstitutes dorsal group-regulated degradation, while fusion protein constructs that lack the first 125 amino acids of Cactus escape dorsal group-dependent degradation. Furthermore, Cactus-lacZ constructs that lack only the putative IkappaB-dependent kinase target-like motif can nevertheless undergo spatially regulated dorsal group-dependent degradation and we have identified the regulatory determinant responsible for dorsal group-dependent degradation of Cactus in the absence of this motif. Taken together, our studies indicate the presence of two distinct redundantly acting determinants in the N terminus of Cactus that direct dorsal group-dependent degradation. Strikingly, the regulatory domain of human IkappaBalpha can also direct polarized degradation of Cactus-lacZ fusion protein.
View details for Web of Science ID 000170604900011
View details for PubMedID 11532919