The long-term goal of this proposal is to develop a novel therapeutic for the prevention of chronic thrombotic conditions (e.g., recurrent stroke, myocardial infarction) in patients with previous history of heart disease. ADP has been implicated as an important platelet activator in hemostasis and arterial thrombosis. The platelet ADP receptor is thought to be expressed only on platelets and megakaryocytes and therefore seems to be an optimal target for drugs modulating platelet activation. The development of high-throughput screening assays for ADP receptor antagonists has been impaired by the unavailability of the receptor cDNA and cell lines overexpressing the receptor.
The specific aim of this Phase I study is to isolate cDNA's for the receptor using Xenopus laevis oocyte expression technology and PCR cloning of novel platelet members of the G-protein coupled receptor superfamily related to known P/2 purinoceptors. Successful completion of this proposal will lead to a Phase II application where we will utilize the receptor cDNA to generate cell lines overexpressing the receptor to develop high-throughput screening assays to detect novel leads derived from a variety of natural product and synthetic compound libraries. The resulting therapeutics should be effective in the treatment and prevention of stroke, peripheral vascular diseases and thrombotic complications following angioplasty and other invasive procedures.
Cloning of the platelet ADP receptor will facilitate the identification of novel leads for platelet-specific antithrombotics with a variety of clinical applications including the treatment and prevention of stroke, unstable angina, peripheral vascular diseases and thrombotic complications following angioplasty and other invasive procedures.
