University of California

The United States Government as Represented by the Department of Veterans Affairs

The J. David Gladstone Institutes

Robert L Raffai

Karl H Weisgraber

Robert V Farese, Jr

Li-Ming Dong

An animal model has been developed where the animals can survive myocardial infarctions caused by diet-induced coronary atherosclerosis, and live with chronic heart failure. This animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and ApoE and the inducible activity of the Mx1-Cre gene. In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR-BI (SRBI) and an impaired ApoE expressor (Apoe) to generate a strain referred to as ApoeSRB1mice, which is then crossbred to mice that carry the inducible Mx1-Cre transgene. The ApoeSRB1mouse model is genetically modified, enabling the offspring to rapidly and permanently lower their high blood cholesterol levels caused by dietary challenge. The ability to rapidly and permanently lower blood cholesterol levels in these mice stops and may cause the regression of occlusive coronary atherosclerosis restoring blood flow to the heart, allowing the mice to survive from myocardial infarction and live with chronic heart failure.

Mouse model of chronic heart failure and coronary atherosclerosis regression

The invention provides gene-targeted non-human animals comprising a genetically modified apoE gene encodes a recombinant apoE polypeptide displaying domain interaction. The invention further provides cells isolated from the gene-targeted animals, which cells produce a recombinant apoE polypeptide displaying domain interaction. The invention further provides methods of identifying agents that reduce apoE4 domain interaction, and which are useful to treat apoE4-related neurological and cardiovascular disorders.

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Half Moon Bay, CA, United States of America

Robert L Raffai