Insulin/IGF-1 Pathway In Barrett´s Esophagus
Amitabh Chak, Associate Professor
Medicinecase Western Reserve University
Grant 5R21CA135692-02 from National Cancer Institute IRG: ZRG1
Abstract: The alarming rise in esophageal adenocarcinoma incidence over the past 3 decades coupled with a poor prognosis make this cancer an important national public health issue. Adenocarcinoma of the esophagus arises in Barrett´s esophagus, a pre- neoplastic metaplastic transformation of the squamous epithelium that is closely associated with gastroesophageal reflux. We, and others, have found that Barrett´s esophagus and esophageal adenocarcinoma are independently linked to obesity. The increased incidence of these diseases is partially attributable to a pandemic of obesity in this country. Increased levels of insulin and the Type 1 insulin growth factor are postulated to be a key mechanistic link between obesity, the Western diet, and carcinogenesis in other cancers. Our central hypothesis is that "hyperinsulinemia and high levels of Type 1 insulin growth factor (IGF-1) possibly related to the Western diet in susceptible individuals contribute to genetic and epigenetic changes in the esophageal epithelium that are key to the development of Barrett´s esophagus and its subsequent progression to esophageal adenocarcinoma". Components of this complex hypothesis will be explored in this case control study whose aims are -- to 1. Calculate insulin resistance and measure free IGF-1; 2. Assay phosphorylated insulin receptor substrate- 1 (phos-IRS-1) immunostaining; and 3. Assess for aberrant methylation of selected candidate genes in Barrett´s esophagus patients and control subjects. Successful conduct of this pilot study will enable future studies which are a) examining the interaction of the insulin/IGF proliferative pathway with gastreoesophageal reflux in esophageal carcinogenesis; b) studies to identify important dietary factors in the development of Barrett´s esophagus; c) risk stratification of Barrett´s esophagus based on biomarkers; and d) trials of potential therapeutic agents based on the insulin/IGF pathway. The research proposed in this application will determine whether increased level of the hormones, insulin and insulin growth factor-1, explain the link between obesity and adenocarcinoma of the esophagus. It will also enable studies to identify factors in the Western diet that might predispose to the development of Barrett´s esophagus and cancer. Furthermore, this research will identify biomarkers that may lead to methods for identifying people with Barrett´s esophagus who are at risk for developing cancer and lead to treatments aimed at halting or reversing this process
Project start date: 2008-07-21
Project end date: 2010-06-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Amitabh Chak
ACUTE PANCREATITIS--A DIAGNOSTIC DILEMMA
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5M01RR000080-360880 from National Center For Research Resources
Abstract: The purpose of this study is to determine the usefulness of a rapid urine amylase test in the diagnosis of acute pancreatitis. The specific aim is to determine the concordance of the rapid urine amylase test in patients with post-ERCP induced hyperamylasemia compared to standard tests in the diagnosis of acute chemical pancreatitis. Results to date indicate that the Rapignost test has high specificity and sensitivity in diagnosing acute pancreatitis in the post-ERCP model of hyperamylasemia.
Keywords: acute disease /disorder, amylase, diagnosis design /evaluation, pancreatitis, urinalysis, cholangiography, diagnosis quality /standard, diagnostic test, pancreas visualization, rapid diagnosis, clinical research, human subject
Project start date: 1997-12-01
Project end date: 1998-11-30
Insulin/IGF-1 Pathway In Barrett´s Esophagus
Amitabh Chak, Associate Professor
Medicinecase Western Reserve University
10900 Euclid Ave
cleveland, Oh 441064919
Grant 1R21CA135692-01A1 from National Cancer Institute IRG: ZRG1
Abstract: The alarming rise in esophageal adenocarcinoma incidence over the past 3 decades coupled with a poor prognosis make this cancer an important national public health issue. Adenocarcinoma of the esophagus arises in Barrett´s esophagus, a pre- neoplastic metaplastic transformation of the squamous epithelium that is closely associated with gastroesophageal reflux. We, and others, have found that Barrett´s esophagus and esophageal adenocarcinoma are independently linked to obesity. The increased incidence of these diseases is partially attributable to a pandemic of obesity in this country. Increased levels of insulin and the Type 1 insulin growth factor are postulated to be a key mechanistic link between obesity, the Western diet, and carcinogenesis in other cancers. Our central hypothesis is that "hyperinsulinemia and high levels of Type 1 insulin growth factor (IGF-1) possibly related to the Western diet in susceptible individuals contribute to genetic and epigenetic changes in the esophageal epithelium that are key to the development of Barrett´s esophagus and its subsequent progression to esophageal adenocarcinoma". Components of this complex hypothesis will be explored in this case control study whose aims are -- to 1. Calculate insulin resistance and measure free IGF-1; 2. Assay phosphorylated insulin receptor substrate- 1 (phos-IRS-1) immunostaining; and 3. Assess for aberrant methylation of selected candidate genes in Barrett´s esophagus patients and control subjects. Successful conduct of this pilot study will enable future studies which are a) examining the interaction of the insulin/IGF proliferative pathway with gastreoesophageal reflux in esophageal carcinogenesis; b) studies to identify important dietary factors in the development of Barrett´s esophagus; c) risk stratification of Barrett´s esophagus based on biomarkers; and d) trials of potential therapeutic agents based on the insulin/IGF pathway. The research proposed in this application will determine whether increased level of the hormones, insulin and insulin growth factor-1, explain the link between obesity and adenocarcinoma of the esophagus. It will also enable studies to identify factors in the Western diet that might predispose to the development of Barrett´s esophagus and cancer. Furthermore, this research will identify biomarkers that may lead to methods for identifying people with Barrett´s esophagus who are at risk for developing cancer and lead to treatments aimed at halting or reversing this process
Project start date: 2008-07-21
Project end date: 2010-06-30
1R21CA135692-01A1 (2008): $195150
PATIENT ORIENTED RESEARCH IN BARRETT S ESOPHAGUS
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 2K24DK002800-06 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Patient oriented research (POR) must translate advances in basic and technical sciences into an increased understanding of disease processes and novel clinical applications that improve patient care. The investigator s long-term career goals are to - 1) encourage POR in gastroenterology; 2) attract and mentor young trainees in POR; and 3) continually enhance his personal POR skills. The K24 mechanism has been instrumental in developing a POR program with a focus on Barrett s esophagus (BE) and esophageal adenocarcinoma (EAC). Successful mentored research projects developed novel low cost methods for BE screening that were subsequently used to demonstrate familial aggregation of BE and EAC. K24 support has also allowed the investigator to mentor nine fellows and seven residents in numerous projects. Many have begun productive academic careers or gastroenterology fellowships. Enrollment in epidemiological and genetic courses has further enhanced the investigator s personal skills in POR. A new R01 project aimed at characterizing familial BE and the identification of the heritable genetic mutation(s) that determine susceptibility to Barrett s esophagus form the major basis of the investigator s ongoing POR program. Novel research investigating a potential link between obesity and BE through the insulin/IGF-1 pathway is proposed in this application. Renewed support will allow the investigator to meet his career goals by - 1) directing and growing POR activities within his division; 2) continuing to attract and mentor residents, fellows, and advanced fellows in his expanding research program; and 3) continuing coursework in statistical genetics and cancer biology.
Keywords: Barretts esophagus, insulin, insulinlike growth factor, obesity, mentoring /mentor, clinical research, human subject, patient oriented research
Project start date: 1999-12-01
Project end date: 2011-06-30
2K24DK002800-06 (2006): $179933
PATIENT ORIENTED RESEARCH IN BARRETT´S ESOPHAGUS
Amitabh Chak, Associate Professor
Medicinecase Western Reserve University
Grant 5K24DK002800-09 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Patient oriented research (POR) must translate advances in basic and technical sciences into an increased understanding of disease processes and novel clinical applications that improve patient care. The investigator´s long-term career goals are to - 1) encourage POR in gastroenterology; 2) attract and mentor young trainees in POR; and 3) continually enhance his personal POR skills. The K24 mechanism has been instrumental in developing a POR program with a focus on Barrett´s esophagus (BE) and esophageal adenocarcinoma (EAC). Successful mentored research projects developed novel low cost methods for BE screening that were subsequently used to demonstrate familial aggregation of BE and EAC. K24 support has also allowed the investigator to mentor nine fellows and seven residents in numerous projects. Many have begun productive academic careers or gastroenterology fellowships. Enrollment in epidemiological and genetic courses has further enhanced the investigator´s personal skills in POR. A new R01 project aimed at characterizing familial BE and the identification of the heritable genetic mutation(s) that determine susceptibility to Barrett´s esophagus form the major basis of the investigator´s ongoing POR program. Novel research investigating a potential link between obesity and BE through the insulin/IGF-1 pathway is proposed in this application. Renewed support will allow the investigator to meet his career goals by - 1) directing and growing POR activities within his division; 2) continuing to attract and mentor residents, fellows, and advanced fellows in his expanding research program; and 3) continuing coursework in statistical genetics and cancer biology
Project start date: 1999-12-01
Project end date: 2011-06-30
5K24DK002800-08 (2008): $178853
5K24DK002800-07 (2007): $178853
Familial Aggregation Of Barrett s Esophagus
Amitabh Chak, Associate Professor
University Hospitals Of Cleveland Lksd 1400 Cleveland, Oh 441065000
Grant 5R03DK061426-02 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Esophageal adenocarcinoma is associated with a very poor prognosis. More effective screening, surveillance, and treatment strategies are required. The overall aim of this pilot proposal is to develop methodologies that will facilitate future multicenter studies aimed at assessing the familial aggregation of Barrett s esophagus and esophageal adenocarcinoma. Three specific methodologies will be developed 1. A multicenter network will be established at five different institutions to enable the measurement of the prevalence of familial Barrett s esophagus. Familial Barrett s esophagus will be identified by administration of a questionnaire that has already been tested at University Hospitals of Cleveland. 2. Methodology will be developed to screen symptomatic first degree relatives of index patients with Barrett s esophagus and esophageal adenocarcinoma. Relatives with gastroesophageal reflux disease who have already been identified at University Hospitals of Cleveland through the study questionnaire will be recruited for screening endoscopy via mailings and phone calls. 3.Methodology will also be developed to recruit and screen asymptomatic or mildly symptomatic first degree using a new battery powered ultrathin endoscope. Successful conduct of this research proposal will result in the creation of a multi-center network, the identification of families with aggregation of Barrett s esophagus and esophageal adenocarcinoma, and the development of methodology for detecting Barrett s esophagus in previously undiagnosed family members. These three achievements will permit future full-scale multi-center epidemiologic and genetic linkage studies with the ultimate goals of measuring the familial risk of Barrett s esophagus and the identification of susceptibility gene(s) that predispose individuals to the development of Barrett s esophagus. The results of these future investigations will aid the development of lower cost, more effective screening and surveillance programs for Barrett s esophagus. They will also define a population at risk in whom interventions to prevent or eradicate Barrett s esophagus can be applied.
Keywords: Barretts esophagus, adenocarcinoma, cancer prevention, cancer risk, carcinogenesis, esophagus neoplasm, family genetics, genetic susceptibility, neoplasm /cancer epidemiology, biomedical equipment development, clinical biomedical equipment, cooperative study, diagnosis design /evaluation, diagnostic test, endoscopy, neoplasm /cancer diagnosis, histopathology, human genetic material tag, human subject, patient oriented research, questionnaire, statistics /biometry
Project start date: 2002-05-01
Project end date: 2005-04-30
5R03DK061426-02 (2003): $119890
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01DK070863-03 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: CIGP
Abstract: Barrett s esophagus is the precursor of esophageal adenocarcinoma. Both Barrett s esophagus and esophageal adenocarcinoma are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophageal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett s esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett s esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Identification of genetic risk factors would lead to more effective screening programs and improved understanding of the molecular pathogenesis of these diseases. Our prior case control study demonstrated familial aggregation of Barrett s esophagus and its associated cancers, which we termed Familial Barrett s Esophagus. We have since developed family recruitment and endoscopic screening methods to identify Familial Barrett s Esophagus. Recent molecular genetic studies have identified one putative locus and suggest the existence of at least one other locus linked to these diseases. These family recruitment, endoscopic screening, and genetic analysis methods will now be used to test the following central hypothesis Familial Barrett Esophagus has a genetic basis. The specific aims of this proposal are (1) To recruit and screen family members of esophageal adenocarcinoma patients, comparing age of cancer onset between probands classified as familial with those classified as apparently sporadic; (2) To perform endoscopic screening and measure the recurrence risk of Barrett s esophagus in siblings of probands with Barrett s esophagus and esophageal adenocarcinoma; and (3) To identify loci and map susceptibility genes associated with Familial Barrett s Esophagus. Using the multidisciplinary approach of our collaborative team of investigators, these aims will result in new information regarding a genetic predisposition to the development of Barrett s esophagus and esophageal adenocarcinoma.
Keywords: Barretts esophagus, cancer risk, esophagus neoplasm, family genetics, genetic susceptibility, adenocarcinoma, disease /disorder onset, genetic mapping, neoplasm /cancer genetics, preneoplastic state, clinical research, endoscopy, genetic screening, human subject
Project start date: 2005-09-30
Project end date: 2010-08-31
5R01DK070863-03 (2007): $748683
5R01DK070863-02 (2006): $745169
1R01DK070863-01 (2005): $756367
Amitabh Chak, Associate Professor
Medicinecase Western Reserve University
Grant 5R01DK070863-05 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: CIGP
Abstract: Barrett´s esophagus is the precursor of esophageal adenocarcinoma. Both Barrett´s esophagus and esophageal adenocarcinoma are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophageal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett´s esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett´s esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Identification of genetic risk factors would lead to more effective screening programs and improved understanding of the molecular pathogenesis of these diseases. Our prior case control study demonstrated familial aggregation of Barrett´s esophagus and its associated cancers, which we termed Familial Barrett´s Esophagus. We have since developed family recruitment and endoscopic screening methods to identify Familial Barrett´s Esophagus. Recent molecular genetic studies have identified one putative locus and suggest the existence of at least one other locus linked to these diseases. These family recruitment, endoscopic screening, and genetic analysis methods will now be used to test the following central hypothesis Familial Barrett Esophagus has a genetic basis. The specific aims of this proposal are (1) To recruit and screen family members of esophageal adenocarcinoma patients, comparing age of cancer onset between probands classified as familial with those classified as apparently sporadic; (2) To perform endoscopic screening and measure the recurrence risk of Barrett´s esophagus in siblings of probands with Barrett´s esophagus and esophageal adenocarcinoma; and (3) To identify loci and map susceptibility genes associated with Familial Barrett´s Esophagus. Using the multidisciplinary approach of our collaborative team of investigators, these aims will result in new information regarding a genetic predisposition to the development of Barrett´s esophagus and esophageal adenocarcinoma
Project start date: 2005-09-30
Project end date: 2010-08-31
5R01DK070863-04 (2008): $755466
3R01DK070863-04S1 (2008): $39995
FAMILIAL FACTORS IN BARRETT S ESOPHAGUS
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5K24DK002800-04 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Advances in basic sciences often translate into an increased understanding of disease processes. Similarly, advances in endoscopic engineering also produce new technology with novel applications in clinical gastroenterology. I believe that patient-oriented researchers in gastrointestinal diseases and gastrointestinal endoscopy must translate advances in basic sciences and engineering technology to improved methods for patient care. Using my previous experience in basic research and training in advanced endoscopy, I have initiated and successfully implemented investigations that address this goal. My research objectives have been furthered by the opportunity to mentor several advanced gastroenterology fellows in the performance of specialized endoscopic procedures and patient-oriented research projects. These trainees are now productive clinical investigators in the field of gastrointestinal endoscopy. Protected time provided by this award will permit me to develop a meaningful research program that focuses on applying new endoscopic techniques and advances in human genetics to the evaluation of Barrett s esophagus and esophageal adenocarcinoma. The award will also further my education in two areas in which it is slightly deficient, viz., biostatistics and human genetics. Educational courses in these subjects and collaborations with experts in these fields will strengthen the development of my research program. Lastly, the award will allow me to teach advanced endoscopy to new trainees and mentor them in the development of their own research projects within my program. Esophageal adenocarcinoma is associated with a very poor prognosis. More effective screening, surveillance, and treatment strategies are required. The aim of the current proposal is to identify familial factors involved in the development of Barrett s esophagus and esophageal adenocarcinoma. The ultimate goal of this research program is to help identify the heritable genetic mutation(s) that determine susceptibility to Barrett s esophagus in order to improve screening and surveillance strategies for this disease.
Keywords: Barretts esophagus, family genetics, genetic susceptibility, adenocarcinoma, longitudinal human study, endoscopy, human subject, patient oriented research
Project start date: 2001-08-15
Project end date: 2006-06-30
5K24DK002800-04 (2004): $132408
FAMILIAL FACTORS IN BARRETT´S ESOPHAGUS
Amitabh Chak, Associate Professor
Medicinecase Western Reserve University
10900 Euclid Ave
cleveland, Oh 44106
Grant 1K24DK002800-01A2 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Advances in basic sciences often translate into an increased understanding of disease processes. Similarly, advances in endoscopic engineering also produce new technology with novel applications in clinical gastroenterology. I believe that patient-oriented researchers in gastrointestinal diseases and gastrointestinal endoscopy must translate advances in basic sciences and engineering technology to improved methods for patient care. Using my previous experience in basic research and training in advanced endoscopy, I have initiated and successfully implemented investigations that address this goal. My research objectives have been furthered by the opportunity to mentor several advanced gastroenterology fellows in the performance of specialized endoscopic procedures and patient-oriented research projects. These trainees are now productive clinical investigators in the field of gastrointestinal endoscopy. Protected time provided by this award will permit me to develop a meaningful research program that focuses on applying new endoscopic techniques and advances in human genetics to the evaluation of Barrett´s esophagus and esophageal adenocarcinoma. The award will also further my education in two areas in which it is slightly deficient, viz., biostatistics and human genetics. Educational courses in these subjects and collaborations with experts in these fields will strengthen the development of my research program. Lastly, the award will allow me to teach advanced endoscopy to new trainees and mentor them in the development of their own research projects within my program. Esophageal adenocarcinoma is associated with a very poor prognosis. More effective screening, surveillance, and treatment strategies are required. The aim of the current proposal is to identify familial factors involved in the development of Barrett´s esophagus and esophageal adenocarcinoma. The ultimate goal of this research program is to help identify the heritable genetic mutation(s) that determine susceptibility to Barrett´s esophagus in order to improve screening and surveillance strategies for this disease
Keywords: Barretts esophagus, family genetics, genetic susceptibility adenocarcinoma, longitudinal human study endoscopy, human subject, patient oriented research
Project start date: 2001-08-15
Project end date: 2006-06-30
1K24DK002800-01A2 (2001): $132408
FAMILIAL FACTORS IN BARRETT S ESOPHAGUS
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5K24DK002800-05 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Advances in basic sciences often translate into an increased understanding of disease processes. Similarly, advances in endoscopic engineering also produce new technology with novel applications in clinical gastroenterology. I believe that patient-oriented researchers in gastrointestinal diseases and gastrointestinal endoscopy must translate advances in basic sciences and engineering technology to improved methods for patient care. Using my previous experience in basic research and training in advanced endoscopy, I have initiated and successfully implemented investigations that address this goal. My research objectives have been furthered by the opportunity to mentor several advanced gastroenterology fellows in the performance of specialized endoscopic procedures and patient-oriented research projects. These trainees are now productive clinical investigators in the field of gastrointestinal endoscopy. Protected time provided by this award will permit me to develop a meaningful research program that focuses on applying new endoscopic techniques and advances in human genetics to the evaluation of Barrett s esophagus and esophageal adenocarcinoma. The award will also further my education in two areas in which it is slightly deficient, viz., biostatistics and human genetics. Educational courses in these subjects and collaborations with experts in these fields will strengthen the development of my research program. Lastly, the award will allow me to teach advanced endoscopy to new trainees and mentor them in the development of their own research projects within my program. Esophageal adenocarcinoma is associated with a very poor prognosis. More effective screening, surveillance, and treatment strategies are required. The aim of the current proposal is to identify familial factors involved in the development of Barrett s esophagus and esophageal adenocarcinoma. The ultimate goal of this research program is to help identify the heritable genetic mutation(s) that determine susceptibility to Barrett s esophagus in order to improve screening and surveillance strategies for this disease.
Keywords: Barretts esophagus, family genetics, genetic susceptibility, adenocarcinoma, longitudinal human study, endoscopy, human subject, patient oriented research
Project start date: 2001-08-15
Project end date: 2006-06-30
5K24DK002800-05 (2005): $132408
5K24DK002800-03 (2003): $132408
Amitabh Chak, Associate Professor
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5P41RR003655-190078 from National Center For Research Resources IRG: ZRG1
Keywords: Barretts esophagus, biomedical facility, family genetics, genetics, clinical research
Project start date: 2004-08-01
Project end date: 2005-07-31