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Cellular Regulation of Human Proximal stomach Motor Responses
Gastric motility defects present as functional dyspepsia or gastroparesis and often arise as complications of obesity and diabetes. The prevalence of diabetic gastroparesis is increasing due to the increasing incidence of obesity and type 2 diabetes in the US. The objective of the proposed project is to establish a better understanding of the cellular basis of human gastric fundus motility to develop more extensive and focused investigations utilizing NIH R01 and/or P01 levels of support. This study will provide the first evaluation of Ca2+ sensitization mechanisms in human gastric fundus smooth muscles activated by acetylcholine (ACh) in its physiological role as a neurotransmitter. The proposed studies will detail the mechanisms by which myofilament sensitivity to Ca2+ is increased by cholinergic neurotransmission, define approaches that can further increase Ca2+ sensitivity, and examine the potential role of interstitial cells of Cajal (ICC) in specifying how the cholinergic signal increases Ca2+ sensitivity. These studies will have relevance to the clinical management of diabetic gastroparesis by providing a better understanding of the mechanism by which the novel cholinesterase inhibitor Acotiamide improves gastric motility and clinical symptoms in patients with functional dyspepsia or gastroparesis. The specific aims are: 1.Determine the importance of Ca2+ sensitization mechanisms for gastric fundus smooth muscle contraction by cholinergic neurotransmission. We will compare Rho kinase and protein kinase C activation by cholinergic neurotransmission and bath application of carbachol by measuring MYPT1 and CPI-17 phosphorylation. We will use the cholinesterase inhibitor neostigmine to define conditions that increase acetylcholine levels and MYPT1 and CPI-17 phosphorylation, and potentiate the contractile responses. 2. Evaluate the contribution of loss of ICC function to altered Ca2+ sensitization pathways in human gastric fundus smooth muscles. We will examine how disrupting the activity of interstitial cells of Cajal with the novel ANO1 inhibitor benzbromarone affects the activation of Ca2+ sensitization pathways in fundus smooth muscles by cholinergic neurotransmission.
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Cellular Regulation of Human Proximal stomach Motor Responses (Perrino, Brian)
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Year: 2019; Items: 1
Quantitative in situ proximity ligation assays examining protein interactions and phosphorylation during smooth muscle contractions.
Xie Y, Perrino BA
, 2019 (577), 1 - 13
Year: 2018; Items: 1
Contractile Protein Expression and Phosphorylation and Contractility of Gastric Smooth Muscles from Obese Patients and Patients with Obesity and Diabetes.
Li W, Sasse KC, Bayguinov Y, Ward SM, Perrino BA
Journal of diabetes research
, 2018 (2018), 8743874
Year: 2016; Items: 1
Calcium Sensitization Mechanisms in Gastrointestinal Smooth Muscles.
Journal of neurogastroenterology and motility
, 2016 (22), 213 - 25
No uploaded documents found.
No protocols found.
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The DiaComp Gastro-Intestinal (GI) Committee has the principal function of furthering the mission of the consortium with regard to diabetic gastro-intestinal (GI) and liver disease
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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