This K24 application has two broad goals: mentoring investigators while pursuing RO1 research (DK 54681). Past mentorship record during prior cycle and plans for future mentoring activities: 1. 24 mentees have worked with candidate in the past 4 years on the K24 grant. One has received two RO1 grants for work in patient-oriented research; three are submitting or have submitted K23 applications in 2002-2003. Candidate was recognized as Outstanding Mentor, Dept of Medicine, Mayo Clinic Rochester (Chair: Nicholas F. LaRusso, M.D.) in 2002. 2. Publication record: >50 original articles were published or submitted by the mentees in the past 4 years. 3. Higher academic degrees conferred on the mentees: 3 completed Masters degrees in Clinical Research (K30 HL04099); two Masters degrees to be completed by July 2003; one Ph.D (examination in first quarter 2003). 4. Leadership in graduate education: Candidate anchors 2 new credit courses in Mayo Graduate School (a. Research Administration and Responsible Conduct of Research; b. Applied Enteric Neuroscience) and is a member of Curriculum Committee for Masters Degree Program (K30-HL04099). 5. Research plan in clinical enteric neurosciences: competitively renewed NIH RO1 grant DK 54681 (2003-7) and single center funding or grant applications (K23) in progress for 8 mentees for the coming 2 years: Drs. HJ Chial, EJ Castillo, A Foxx-Orenstein, F Cremonini, D Chitkara, J Gonenne, and LA Szarka (Mayo) and CM Prather (St Louis University). 6. Training and educational experiences provided to mentees: Theoretical and technical training in patient-oriented research: mechanisms of sensorimotor dysfunction of the digestive tract. Scientific Plan: Irritable bowel syndrome (IBS) is a common condition, characterized by heightened visceral sensitivity and/or abnormal motor function. The adrenergic nervous system modulates gastrointestinal functions in health and in IBS. Subgroups with high vs. no response to clonidine in IBS patients suggest a role for adrenergic genotypes in determining the response in patients. In preliminary studies (performed as specific aim 4 of the previous grant cycle) of 274 patients and 120 ethnically matched healthy controls, two functionally distinct polymorphisms were independently associated with the phenotype IBS-constipation: alpha2c Ncil odds ratio, OR : 2.48, CI 0.98 - 6.28, [p=0.05] and alpha2A Msp1 OR: 1.66, CI 0.94 - 2.92, [p=0.08] relative to wild type genotype. Accurate, thorough phenotypic characterization of patients with IBS and their responses to clonidine are essential for pharmacogenomic studies. Our overall objective is to characterize in IBS patients the relationship between the phenotypic response to clonidine and genetic variations in noradrenergic and alpha2-adrenergic control using a candidate gene analysis approach.
Aims : 1. To characterize whole gut transit, rectal sensory and motor functions, gastric volumes, postprandial abdominal symptoms and central and peripheral adrenergic functions in 120 patients with IBS and 40 controls. 2. To study the effects of acutely administered 0.1 or 0.15 mg clonidine (p.o.) on gastrointestinal functions in IBS patients and controls. 3. To assess relationship between responses in the gut to clonidine and polymorphisms of the alpha2A-and alpha2c-adrenergic receptors, and mutations in norepinephrine transporter. 4. To assess the feasibility of recruiting African-American IBS patients and controls from other medical centers to obtain preliminary data on symptom phenotype and adrenergic genotype. Significance: This project will characterize pharmacogenetic mechanisms determining the response to clonidine through studies of candidate genes that control alpha2-adrenoreceptor function and norepinephrine transport in IBS.
Showing the most recent 10 out of 153 publications
