New England Medical Center Hospitals. Inc.

Other

Michael E Mendelsohn

Richard H Karas

Howard K Surks

The present invention relates to screening methods that make use of Myosin Phosphatase-Rho interacting Protein (M-RIP) for the identification of novel therapeutics for hypertension and hypertensive conditions. Also disclosed are methods for treating or preventing hypertension or hypertensive conditions by administering to a mammal a therapeutically effective amount of an agent that reduces the level or activity of M-RIP. According to this invention, the agent decreases contractile and increases relaxant effects of smooth muscle cells, ultimately decreasing the systemic blood pressure of a mammal. For example, the agent may reduce binding of M-RIP to myosin phosphatase, RhoA, or both.

Compositions involving M-RIP, and related methods for screening for anti-hypertensive agents, and uses thereof

The invention provides a method for assaying compounds that affect cell division by determining the interaction between estrogen receptor ER&#x3b2; and MAD2, a cell cycle checkpoint protein.

Method for assaying compounds affecting cell division using estrogen receptor beta (ER&#x3b2;) and mitosis arrest deficient 2 (MAD2)

The invention features assays to identify cardiovascular agents, such as vasoprotective agents, antihypertensive agents, cardiomyopathy therapeutic agents, coronary heart disease therapeutic agents, or heart failure therapeutic agents. The assays include culturing cells in the presence or absence of a predetermined amount of the candidate agent and measuring the expression or activity of selected genes or reporter constructs known to be responsive to estrogen.

Methods for identifying cardiovascular agents

The invention features screening methods which can be used to identify agents, known as vasoprotective agents, which inhibit vascular smooth muscle cell activation and/or proliferation or enhance vascular endothelial cell activation and/or proliferation or activate estrogen responsive genes in vascular cells. Preferred vasoprotective agents are relatively vasospecific, i.e., their effect on one or more types of vascular cells is more pronounced than their effect on other cell types. Treatment with such vasospecific agents will generally be associated with fewer undesirable side-effects than treatment with estrogen. The methods of the invention are screening assays in which candidate agents are examined to identify vasoprotective agents. One type of screening assay involves examining the effect of a candidate agent on cell proliferation and/or cell activation. Another type of screening assay involves examining the effect of a candidate agent on the expression of a gene which is responsive to estrogen. Both screening assays involve the use of vascular cells and non-vascular cells. The use of both cell types is important because the cellular milieu is very likely to influence the effect of a candidate agent on cell proliferation, cell activation, and the expression of an given estrogen receptor responsive gene.

Methods for identifying vasoprotective agents

The invention features methods for assaying compounds that affect the activation of a cell. The methods include measurement of cell activation, G protein-coupled receptor phosphorylation, or phosphorylation of proteins associated with the G-protein-coupled receptor, in a system comprising G protein-coupled receptor-bearing cells, or preparations thereof, cyclic GMP, or analogs thereof, and cyclic GMP-dependent protein kinase.

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Wellesley, MA, United States of America

Michael E Mendelsohn