Mouse Models Having a Knockin Scavenger Receptor Class B Type I

A mouse model for a disease or condition selected from the group consisting of:

• hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease;
• wherein the mouse model is fed a regular laboratory diet or an atherogenic diet, wherein the mouse model is a female mouse or a male mouse, wherein said mouse model expresses a truncated or mutated form of SR-BI in one or more tissues, and has a decreased activity or expression of SR-BI in one or more tissues, as compared to that in a wild-type mouse, and decreased protein activity or decreased gene expression or decreased protein expression of wild-type or mutant forms of apolipoprotein E, as compared to that in a wild-type mouse, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• a. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6 and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6 that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• b. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• c. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• d. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of full-length, wild-type SR-BI and wherein the female mouse model is fertile.

A mouse model for a disease or condition selected from the group consisting of:

• hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease;
• wherein the mouse model is fed a regular laboratory chow diet or an alternative diet compatible with the long-term survival of wild-type mice, wherein the mouse model is a female mouse or a male mouse, wherein said mouse model a homozygous alternation or compound heterozygous alteration in the SR-B1 gene that expresses a truncated or mutated form of SR-BI protein in one or more tissues, and a homozygous disruption of the apolipoprotein E gene resulting in loss of apolipoprotein E activity, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• a. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6 and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6 that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissue as compared to wild-type SR-BI protein;
• b. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• c. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• d. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of SR-BI.

A mouse model for a disease or condition selected from the group consisting of:

• hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease;
• wherein the mouse model is induced by feeding an atherogenic diet, wherein the mouse model is a female mouse or a male mouse, wherein said mouse model expresses a truncated or mutated form of SR-BI in one or more tissues, and has a decreased activity or expression of SR-BI in one or more tissues, as compared to that in a wild-type mouse, and decreased activity or expression to 2-5% of apolipoprotein E, as compared that in a wild-type mouse, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• a. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6 and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6 that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• b. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• c. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• d. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI has reduced activity in one or more tissues as compared to wild-type SR-BI protein ;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of SR-BI and wherein the female mouse is fertile.

A mouse model for a disease or condition selected from the group consisting of:

• hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease;
• wherein the mouse model is induced by feeding an atherogenic diet, wherein the mouse model is a female mouse or a male mouse, wherein said mouse model expresses a truncated or mutated form of SR-BI in one or more tissues, and has a decreased activity or expression of SR-BI in one or more tissues, as compared to that in a wild-type mouse, and a decreased activity or expression of LDLR, as compared that in a wild-type mouse, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• a. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6, and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6 that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• b. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• c. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• d. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of SR-BI and wherein the female mouse is fertile.

A method for screening for compounds having an effect on a disease or condition selected from the group consisting of hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease comprising:

• a. administering the compound to a mouse model that expresses a truncated or mutated form of SR-BI in one or more tissues, and has a decreased activity or expression of SR-BI in one or more tissues, as compared to that in a wild-type mouse, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• i. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6, and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6, that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• ii. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• iii. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• iv. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of wild-type SR-BI;
• wherein the mouse model has a decreased activity or expression of apolipoprotein E, Low-Density Lipoprotein Receptor (LDLR), or both, as compared to that in a wild-type mouse, and wherein the female mouse is fertile;
• b. determining the effect of the compound on the disease or condition in the mouse model, relative to control mice not treated with compound or control mice treated with the compound.

A compound having an effect on a disease or condition selected from the group consisting of hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, vascular disease, arterial thrombosis, deep vein (venous) thrombosis, atherosclerosis, atherothrombosis, rapid onset and fatal, occlusive coronary arterial atherosclerosis and coronary heart disease, wherein the compound is obtained by:

• c. administering the compound to a mouse model that expresses a truncated or mutated form of SR-BI in one or more tissues, and has a decreased activity or expression of SR-BI in one or more tissues, as compared to that in a wild-type mouse, wherein the mouse model is a SR-BI knock-in mouse model, and wherein the truncated or mutated form of SR-BI consists essentially of:
• i. an amino acid sequence of 1-464 of SEQ ID NO:
• 2, 4, or 6 and amino acid sequence of 465-509 of SEQ ID NO:
• 2, 4, or 6 that is removed, truncated, or mutated such that the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• ii. an amino acid sequence encoded by a nucleic acid molecule of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• iii. an amino acid sequence encoded by a complement of 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues, as compared to wild-type SR-BI protein;
• iv. an amino acid sequence encoded by mRNA molecule derived from 1-1392 of SEQ ID NO:
• 1, 3, or 5, and nucleic acid sequence of 1393-1527 of SEQ ID NO:
• 1, 3, or 5 that is removed, truncated, or mutated such that when encoded, the truncated or mutated form of SR-BI protein has reduced activity in one or more tissues as compared to wild-type SR-BI protein;
• wherein the truncated or mutated form of SR-BI protein does not bind to one or more adaptor proteins that recognize the C-terminus of SR-BI;
• wherein the mouse model has a decreased activity or expression of apolipoprotein E, Low-Density Lipoprotein Receptor (LDLR), or both, as compared to that in a wild-type mouse, and wherein the female mouse is fertile;
• d. determining the effect of the compound on the disease or condition in the mouse model, relative to control mice not treated with compound.