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Contenido archivado el 2024-05-14

A2b adenosine receptors in cardiovascular pathology from medicinal chemistry to molecular genetics

Objetivo

Objectives:
The research objectives of the project are to identify the specific function of the A2B adenosine receptor, to characterize the role of its signaling pathway in the control of ischemia-induced tissue degeneration, to evaluate the potential of this receptor subtype as a target for therapeutic intervention in different ischemia-related diseases, and the development of pharmacological tools that will serve as leads for therapies targeting A2B adenosine receptors.

Adenosine is a particularly important endogenous in vivo modulator of ischemia. Once denoted "The Signal of Life", it is a messenger that is released in emergency situations such as ischemia and serves to control ischemia-induced damage by an increasing energy supply and a decreasing energy demand. In this context, the A2B adenosine receptor may be of pivotal significance because it is activated by pathological concentrations of adenosine and it is ubiquitously expressed. This adenosine receptor subtype is, therefore, of major interest as potential target for pharmacological intervention. The fact that beyond its existence almost nothing is known about this receptor subtype prompted us to attempt in a multidisciplinary approach to identify the pathophysiological role of A2B adenosine receptors and to develop tools that, by interacting with this receptor, allow for modulation of the pathophysiology of various ischemicstates. It is the ultimate goal of the current proposal to unravel the still elusive function of A2B adenosine receptors with an approach combining molecular genetics, biochemical pharmacology and medicinal chemistry. Transgenic animals over expressing this receptor and knockout mice that will be generated during the course of the proposed work will serve as valuable models to identify the role of A2B receptors and to study the development and treatment of ischemic diseases.

As a complementary approach, selective high affinity agonists and antagonists will be developed, which will help to verify in normal animals the observations made with transgenic animals. In addition, these ligands will provide tools that allow for selective modulation of cardiovascular pathology via these receptors. Ultimately, these ligands will be of interest as leads for the development of novel drugs. As a result of the Concerted Action ADEURO sponsored by the European Commission the participants of this proposal decided to put together their expertise in an integrated effort to achieve such a goal. The potential benefit of the identification of the function of A2B adenosine receptors is twofold: it would add to the understanding of the complex role of adenosine in cardiovascular physiology and pathophysiology; and new therapeutic concepts could be established that may help to control or even prevent a variety of ischemia-related diseases that are currently leading causes of death. Along these lines, companies have documented their interest in our endeavour develop pharmacological tools to control ischemia.

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Coordinador

Bayerische Julius-Maximilians-Universität Würzburg
Aportación de la UE
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Dirección
Versbacher Straße
97078 Würzburg
Alemania

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Participantes (2)

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