Therapeutic Targeting Of CD40L-Mac-1 In Inflammatory Disease, In Particular Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$559,642.00
Summary
Atherosclerosis is a major burden for human health resulting in myocardial infarction-stroke. We have previously identified a novel interaction between two adhesion molecules, CD40L and Mac-1, which mediates leukocyte adhesion to endothelial cells being a major determinant of atherosclerotic plaque development. We are now developing blocking peptides and recombinant antibodies thereby exploring various anti-inflammatory- anti-atherosclerotic strategies, targeting both Mac-1 and CD40L.
How Does The Mitochondria Regulate Cardiac L-type Ca2+ Channel Function?
Funder
National Health and Medical Research Council
Funding Amount
$328,267.00
Summary
Oxygen is vital to cellular metabolism and function. Oxygen delivery to cells is critical and a lack of oxygen such as occurs during a heart attack can be lethal. The L-type Ca2+ channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into heart muscle cells. It plays a role in maintaining the heart beat and contraction. We have found that a lack of oxygen (hypoxia) alters the function of the L-type Ca2+ channel and its response to adrenergic st ....Oxygen is vital to cellular metabolism and function. Oxygen delivery to cells is critical and a lack of oxygen such as occurs during a heart attack can be lethal. The L-type Ca2+ channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into heart muscle cells. It plays a role in maintaining the heart beat and contraction. We have found that a lack of oxygen (hypoxia) alters the function of the L-type Ca2+ channel and its response to adrenergic stimulation (adrenaline).This may be one of the ways that rhythm disturbances or sudden cardiac death occurs with a heart attack. The activity of the L-type Ca2+ channel is sensitive to changes in reactive oxygen species caused by changes in oxygen concentration. The reactive oxygen species are generated from a part of the cell responsible for maintaining the cell's energy requirements (the mitochondria). Oxidative stress is a feature of various cardiovascular pathologies and we are now interested in determining the effect of oxidative stress on function of the L-type Ca2+ channel and the role of the mitochondria in generating reactive oxygen species. Oxidative stress can damage mitochondria leading to an increase in production of reactive oxygen species. We will determine how oxidative stress damages the mitochondria and how this then alters the channel function, directly or indirectly. The information gained will provide insight into how reactive oxygen species influence L-type Ca2+ channel function and the mechanisms that contribute to pathology involving reactive oxygen species such as heart failure and arrhythmia.Read moreRead less
Novel Selective Anti-platelet And Clot-specific Anticoagulant Strategies Targeting Conformational States Of GPIIb/IIIa
Funder
National Health and Medical Research Council
Funding Amount
$496,517.00
Summary
The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding compl ....The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding complications are also a major financal burden for our health care system. Thus, progress towards therapeutic strategies with less bleeding complications is highly sought-after. The proposed project aims to generate new antibody-based agents for platelet inhibition. One group of these agents do only block platelets when they are activated. Furthermore, these agents allow an enrichment of potent inhibitors of coagulation factors at the site of the clot. Thus, these inhibitors should predominatly act at the site where they are needed. At the same time the overall concentration of inhibitors of coagulation factors can be kept low and the functions of non-activated platelet can be left intact. Overall, the proposed project aims for the development of novel anti-platelet and anticoagulant strategies with high anti-thrombotic efficacy and low bleeding risks.Read moreRead less
A Novel Ionic Current Contributing To Spasm Of Small Blood Vessels
Funder
National Health and Medical Research Council
Funding Amount
$287,500.00
Summary
Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a n ....Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a novel membrane current which we refer to as the plateau current. This current has a strong depolarizing influence that is likely to make a major contribution to the spasms, particularly in arterioles and small arteries which are more dependent on depolarization for contraction. Block of this current is expected to minimize the depolarization and therefore prevent or ameliorate spasm of the vessels. Thus the plateau current represents a new field of therapeutic potential for addressing vascular problems that have significant health implications. However, therapeutic manipulation of the current requires knowledge of its properties. In this project we will determine the biophysical and pharmacological properties of this current using voltage-clamp techniques. We will then use this information to assess its functional significance by recording membrane potential with intracellular microelectrodes simultaneously with contractile activity. We will also compare small vessels obtained from volunteers with or without the vasospastic disorder of Raynaud's phenomenon. Our previous work using these techniques was described in J Physiol as a microelectrode, patch clamp and myograph study of the highest quality and of supreme technical difficulty and scored a Top-Ten hit rate. Since we are the only ones to record the plateau current, we are in a unique position to make significant progress to our understanding of contraction, including spasm, in small blood vessels.Read moreRead less