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High-probability grants
According to our matching algorithm, Wohaib Hasan is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2011 — 2012 |
Hasan, Wohaib |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Attenuation of Cardiac Parasympathetic Nerve Acetylcholine Release in Obesity By @ Oregon Health &Science University
DESCRIPTION (provided by applicant): Obesity can lead to several cardiovascular problems including hypertension and left ventricular hypertrophy. In addition, increased heart rate and plasma catecholamines, and reduced heart rate variability in obesity are due to altered cardiac autonomic control including increased sympathetic and reduced parasympathetic, activity. Abnormal autonomic drive is a causal factor in hypertension and congestive heart failure, and may similarly promote cardiovascular disturbances in obesity. Neuropeptides such as neuropeptide Y (NPY) and galanin, released from sympathetic terminals in the heart, can inhibit acetylcholine release from adjacent parasympathetic nerves. Increased sympathetic drive in obesity may therefore augment neuropeptide release from atrial nerves, thereby promoting the inhibition of acetylcholine release from parasympathetic terminals. This study examines the role of sympathetic neuropeptides in inhibiting both short-term release, and long-term synthesis, of the parasympathetic neurotransmitter acetylcholine in the diet-induced obesity-prone rat heart. An atrial explant system will be utilized to stimulate release of neurotransmitters and neuropeptides from atrial terminals and these proteins will be measured with a sensitive HPLC-MS method. The development of a non-radioactivity based, sensitive assay for simultaneous measurements of absolute levels of neurotransmitters and neuropeptides, is an important novel approach that will be established through this study. We will also co-stimulate autonomic peripheral outflow in vivo to examine functional consequences of parasympathetic disturbances in obesity. Laser capture microdissection of parasympathetic cardiac ganglion neurons followed by qRT-PCR will allow examination of cholinergic marker genes in obesity. Cultured cardiac ganglion neurons will have neuropeptide receptor genes knocked down to examine neuropeptide regulation of acetylcholine synthesis and transport. Attenuated parasympathetic function can result in dysregulated heart rate control, potential for arrhythmias and indirectly contribute to myocardial dysfunction from catecholamine toxicity and increased workload. These studies should identify novel neuropeptide targets for reversing abnormal parasympathetic activity in obese subjects. In addition, a sensitive HPLC-MS method for simultaneous determination of neurochemicals will be developed. PUBLIC HEALTH RELEVANCE: Some cardiovascular complications of obesity may be caused by an imbalance between the autonomic nerves that project to the heart and control heart rate. This study aims to develop sensitive assays for measurement of proteins released by nerves in the heart. Therapeutic sites in the peripheral nervous system may be identified as a result of these studies for reversing detrimental cardiovascular function in obesity.
|
1 |
2018 — 2020 |
Hasan, Wohaib |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuropeptides Reduce Thrombosis Risk in Heart Failure @ Cedars-Sinai Medical Center
Project Summary In chronic heart failure patients, thromboembolic events are the most common complication, resulting in increased hospitalization rates and mortality. Prevention of cardiac thrombosis in heart failure (HF) patients with anticoagulant therapy is controversial because of the increased risk of bleeding. Cardiac endothelial cells normally promote anticoagulation through multiple pathways including activated protein C (APC) generation on their luminal surface. In HF, the endothelial surface becomes increasingly prothrombotic partly due to altered endothelial anticoagulation. Alterations in APC and thrombin generation, and increased von Willebrand factor (vWF) extrusion from the endothelium, are likely consequences of a prothrombotic endothelium. A recombinant form of APC has been used in clinical trials but is associated with an increased risk of bleeding. An alternative therapeutic approach may involve promotion of multiple endogenous endothelial anticoagulant pathways. Cardiac sympathetic nerves make close appositions with endocardial endothelial cells (EECs) that line the cardiac chambers; these direct connections are unlike those with vascular endothelium where smooth muscle separates nerve from endothelial cell. Sympathetic nerves regulate many aspects of normal endothelial function likely through release of norepinephrine (NE) and neuropeptides such as neuropeptide Y (NPY) and galanin. We suspect that neuropeptides promote the anticoagulant function of endothelial cells. We hypothesize that neuropeptide release is suppressed in HF promoting endothelial dysfunction and a reduction in anticoagulation function. We test this hypothesis with human HF and control ventricular tissue and plasma, and in a mouse model of HF. We will determine: (i) the spatial and functional link between endocardial thrombosis and aberrant ventricular innervation; examined in HF mice with a novel combined contrast-enhanced ultrasound and microPET approach; (ii) the mechanisms, both direct and indirect, through which neuropeptides promote endothelial anticoagulation; examined in cultured human heart failure EECs; (iii) the promotion of endothelial anticoagulant function by neuropeptide treatment in vivo in HF mice; (iv) whether plasma neuropeptide levels in HF subjects can be used as early biomarkers of a prothrombotic state. Significance: A critical link between subendocardial nerve activity and endothelial anticoagulant function will be identified in these studies. Preliminary data suggest that neuropeptides promote endothelial anticoagulant function, and this function is disrupted in HF. If this is the case, neuropeptide treatment may provide a novel therapy for reducing thromboembolic complications in HF patients. Establishing a relationship between circulating neuropeptide levels and thrombus formation will identify novel early biomarkers of thromboembolic risk in HF patients.
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0.907 |