Victor Chang Cardiac Research Institute

About: Victor Chang Cardiac Research Institute is a nonprofit organization based out in Sydney, New South Wales, Australia. It is known for research contribution in the topics: Mechanosensitive channels & Heart failure. The organization has 708 authors who have published 1599 publications receiving 70035 citations.

Identifying ligands at orphan GPCRs: current status using structure-based approaches.

Abstract: GPCRs are the most successful pharmaceutical targets in history. Nevertheless, the pharmacology of many GPCRs remains inaccessible as their endogenous or exogenous modulators have not been discovered. Tools that explore the physiological functions and pharmacological potential of these 'orphan' GPCRs, whether they are endogenous and/or surrogate ligands, are therefore of paramount importance. Rates of receptor deorphanization determined by traditional reverse pharmacology methods have slowed, indicating a need for the development of more sophisticated and efficient ligand screening approaches. Here, we discuss the use of structure-based ligand discovery approaches to identify small molecule modulators for exploring the function of orphan GPCRs. These studies have been buoyed by the growing number of GPCR crystal structures solved in the past decade, providing a broad range of template structures for homology modelling of orphans. This review discusses the methods used to establish the appropriate signalling assays to test orphan receptor activity and provides current examples of structure-based methods used to identify ligands of orphan GPCRs. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

Genes and atrial fibrillation: a new look at an old problem.

Abstract: Atrial fibrillation (AF) is an abnormality of the heart’s rhythm that is characterized by rapid and irregular activation of the atria. AF was first described in humans in 19061 and is now recognized to be the most common sustained cardiac arrhythmia and a major public health burden.2 The loss of coordinated atrial contraction results in reduced ventricular filling and blood stasis in the atria, which predispose to heart failure and thromboembolic stroke, respectively.3,4 AF accounts for 15% of all strokes and one third of strokes in individuals >65 years of age.4 AF is also an independent risk factor for death, with a relative risk over all age groups of 1.5 for men and 1.9 for women.5 The prevalence of AF increases with age, ranging from 80 years old.6 Given our aging population, together with contemporary increases in the incidence of risk factors for AF, the numbers affected and the hospitalization and treatment costs are predicted to increase markedly in the future.2 These observations underscore the need for a better understanding of the pathophysiological basis of AF and for the development of new approaches to prevention and management. AF is frequently observed as a complication of diverse cardiac and systemic disorders, including hypertension, coronary artery disease, valvular heart disease, and cardiomyopathies. Hence, AF has traditionally been regarded as a sporadic, nongenetic disorder. In approximately 10% to 20% of cases, an underlying cause cannot be identified, and AF is termed “idiopathic” or “lone.”7 One hundred years on, there is now accumulating evidence that genetic factors have a role in the pathogenesis of AF in a significant proportion of cases. The genes involved and the mechanisms by which defects in these genes alter atrial electrophysiological properties …

Transgenic α1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival

Abstract: Objective: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression ofthe α1A-adrenergic receptors (α1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). Methods: We subjected α1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. Results: Although infarct size was similar in the NTG and α1A-TG groups (32±2 vs. 29±2% of LV, P=NS), mortality due to heart failure was lower after MI in the α1A-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and α1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30±2 to 18±1%, P<0.01) and LVDd (increased by 24%, from 4.2±0.1 to 5.2±0.1 mm, P<0.01), the changes in both FS (fell by 14%, from 42±2 to 36±2%) and LVDd (increased by 8%, from 3.8±0.1 to 4.1±0.1 mm, both changes P<0.01 vs. NTG) were significantly less severe in the α1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dtmax in the α1A-TG vs. NTG mice (7270±324, vs. 5938±372 mmHg/s, P<0.05). Conclusion: Enhanced inotropy resulting from transgenic overexpression of α1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.

FishNet: an online database of zebrafish anatomy

Abstract: Over the last two decades, zebrafish have been established as a genetically versatile model system for investigating many different aspects of vertebrate developmental biology. With the credentials of zebrafish as a developmental model now well recognized, the emerging new opportunity is the wider application of zebrafish biology to aspects of human disease modelling. This rapidly increasing use of zebrafish as a model for human disease has necessarily generated interest in the anatomy of later developmental phases such as the larval, juvenile, and adult stages, during which many of the key aspects of organ morphogenesis and maturation take place. Anatomical resources and references that encompass these stages are non-existent in zebrafish and there is therefore an urgent need to understand how different organ systems and anatomical structures develop throughout the life of the fish. To overcome this deficit we have utilized the technique of optical projection tomography to produce three-dimensional (3D) models of larval fish. In order to view and display these models we have created FishNet http://www.fishnet.org.au , an interactive reference of zebrafish anatomy spanning the range of zebrafish development from 24 h until adulthood. FishNet contains more than 36 000 images of larval zebrafish, with more than 1 500 of these being annotated. The 3D models can be manipulated on screen or virtually sectioned. This resource represents the first complete embryo to adult atlas for any species in 3D.