Gastroparesis (GP) presents with chronic upper GI dysmotility symptoms in the setting of delayed gastric emptying without any mechanical obstruction. Inconsistencies exist between subjective symptom severity and objective evidence of GP, and available therapies are limited by accompanying adverse events and unpredictable efficacy. Hence the pathophysiology, clinical course, outcomes and treatment strategies require further investigation. Our response to the NIDDK Gastroparesis Consortium (U01) under RFA-DK-16-010 has the following aims: 1) To complete approved studies initiated by the GpCRC which entails enrolling GP patients to Gastroparesis Registry 2 with their clinical data and bio-samples as well as obtain gastric tissue under the pathological basis of gastroparesis (PBG) protocol, when some patients undergo surgery for failed medical therapy. This data collection will contribute more knowledge about pathogenesis, pathomorphology, symptoms severity grading, complications, treatment outcomes in patients with GP and gastroparesis-like presentation but normal gastric emptying. 2) As a new diagnostic strategy, we propose to determine whether endoscopic ultrasound (EUS)- guided core biopsy samples of antral muscularis propria in GP patients can provide sufficient tissue for full histologic analysis to specifically address status of interstitial cell of Cajal, myenteric plexus neurons and smooth muscle pathology. After reconfirming the safety and success of this methodology in a study of 30 patients receiving both endoscopic and surgical biopsies all patients entering GpR3 as well as GpR2 registry will undergo EUS guided core biopsies of the antral muscularis propria as part of the database. Therefore we will investigate whether this endoscopic method can safely replace surgery to obtain smooth muscle tissue and correlate ICC findings with symptoms, gastric emptying and treatment outcome. 3) We propose to investigate the therapeutic efficacy of a new Dopamine D2/D3 antagonist in gastroparetic patients of either diabetic or idiopathic etiology by performing a multicenter, double- blind, randomized, placebo-controlled, parallel three-group study which will also assess cardiac safety and adverse event. The plan is for the NIH to partner with one of the 2 pharmaceutical companies developing new agents, Dopamine D2/D3 antagonists with no cardiac toxicity. All GpR3 patients will be invited to enroll into 2 parallel 12 week trials for diabetic and idiopathic etiologies of gastroparesis. If we are awarded this grant, TTU research team is committed to facilitate the execution of the protocols and collaborate with other Centers under GpCRC and NIDDK/NIH supervision.

Public Health Relevance

In the last 20 years, we have learned that gastroparesis affects approximately 10% of US population (>30 million people), who suffer with severe symptoms of nausea, vomiting, inability to finish normal size meal, fullness and abdominal pain, and that diabetic patients are at increased risk. Extensive studies have increased our understanding of this condition, its complications, diagnostic challenges and clinical outcomes, but treatments with new drugs, surgically implanted stimulating devices and even acupuncture approaches have not helped all patients. Because there are many remaining questions and unmet needs which require further examination and clarifications, we have designed two new clinical studies: 1- looking for the reason why the stomach muscle doesn't work effectively in certain patients; and 2- investigating how not yet available new drug may help to reduce symptoms of gastroparesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK074035-12
Application #
10021025
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Serrano, Jose
Project Start
2008-09-30
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Texas Tech University Health Sciences Center at El Paso
Department
Type
DUNS #
962545658
City
El Paso
State
TX
Country
United States
Zip Code
79905
Hasler, W L; May, K P; Wilson, L A et al. (2018) Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis. Neurogastroenterol Motil 30:
Pasricha, Pankaj J; Yates, Katherine P; Sarosiek, Irene et al. (2018) Aprepitant Has Mixed Effects on Nausea and Reduces Other Symptoms in Patients With Gastroparesis and Related Disorders. Gastroenterology 154:65-76.e11
Siraj, Elias S; Homko, Carol; Wilson, Laura A et al. (2018) Islet Cell Associated Autoantibodies and C-Peptide Levels in Patients with Diabetes and Symptoms of Gastroparesis. Front Endocrinol (Lausanne) 9:32
Orthey, Perry; Yu, Daohai; Van Natta, Mark L et al. (2018) Intragastric Meal Distribution During Gastric Emptying Scintigraphy for Assessment of Fundic Accommodation: Correlation with Symptoms of Gastroparesis. J Nucl Med 59:691-697
Parkman, H P; Hallinan, E K; Hasler, W L et al. (2017) Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing. Neurogastroenterol Motil 29:
Gibbons, Simon J; Grover, Madhusudan; Choi, Kyoung Moo et al. (2017) Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis. PLoS One 12:e0187772
Grover, M; Bernard, C E; Pasricha, P J et al. (2017) Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum. Neurogastroenterol Motil 29:
Koch, K L; Hasler, W L; Yates, K P et al. (2016) Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes. Neurogastroenterol Motil 28:1001-15
Parkman, H P; Hallinan, E K; Hasler, W L et al. (2016) Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis. Neurogastroenterol Motil 28:1902-1914
Neshatian, L; Gibbons, S J; Farrugia, G (2015) Macrophages in diabetic gastroparesis--the missing link? Neurogastroenterol Motil 27:7-18

Showing the most recent 10 out of 34 publications