American National Red Cross

Novartis Ag

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Musc Foundation for Research Development

Steingrimur P Stefansson

Daniel Lawrence

Alan Thomas Remaley

Gene Liau

Bryan H Brewer

William S Argraves

Samar Hammad

Joseph Su

The present invention provides an isolated mammalian receptor which specifically binds a high density lipoprotein holoparticle, comprising a subunit of approximately 45-600 kDa molecular weight and one or more subunits selected from the group consisting of a subunit of approximately 40-50 kDa molecular weight, a subunit of approximately 120 kDa molecular weight and a subunit of approximately 400 kDa molecular weight. In addition, the present invention provides a method of screening a substance for the ability to modulate the HDL holoparticle binding and/or internalization activity of the receptor of this invention, comprising: a) contacting the substance with a cell producing a functional HDL receptor; and b) assaying the cell for a modulation of the HDL holoparticle binding and/or internalization activity of the receptor, whereby a modulation of the HDL holoparticle binding and/or internalization activity of the receptor identifies a substance with the ability to modulate the HDL holoparticle binding and/or internalization activity of the ADL receptor.

Methods and compositions for HDL holoparticle uptake receptor

A method of inducing blood vessel formation in an animal by administering to the animal a polynucleotide encoding a sphingosine kinase, or an analogue, fragment, or derivative thereof. The polynucleotide may be contained in an appropriate expression vector, such as a viral vector. The delivery of sphingosine kinase through administration of an expression vector which expresses sphingosine kinase provides for the formation of larger blood vessels containing a well defined structure that is supported by mural cells such as pericytes and smooth muscle cells.

Induction of blood vessel formation through administration of polynucleotides encoding sphingosine kinases

Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids.

Mutant plasminogen activator-inhibitor type 1 (PAI-1) proteins

Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration. These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids.

Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof

Growing community of inventors

Gaitherburg, MD, United States of America

Steingrimur P Stefansson