Abstract: The present invention relates generally to the Tlr4 signaling pathway specifically in the hematopoietic system and its contribution to insulin resistance of liver and adipose tissue. The hematopoietic component expressing Tlr4 is a principle propagator of immune signaling and results in insulin resistance. Furthermore, disclosed herein are methods and compositions for treating or preventing disorders associated with insulin resistance using a Tlr4 antagonist.

Abstract: The invention provides a chimeric CNS targeting polypeptide having a BBB-receptor binding domain and a payload polypeptide domain. The chimeric CNS targeting polypeptide can have a BBB-receptor binding domain consisting of a receptor binding domain from ApoB, ApoE, aprotinin, lipoprotein lipase, PAI-1, pseudomonas exotoxin A, transferrin, ?2-macroglobulin, insulin-like growth factor, insulin, or a functional fragment thereof. Nucleic acids encoding a chimeric CNS targeting polypeptide are also provided. Further provided is a method of delivering a polypeptide to the CNS of an individual. The method consists of administering to the individual an effective amount of a chimeric CNS targeting polypeptide, said chimeric CNS targeting polypeptide comprising a BBB-receptor binding domain and a payload polypeptide domain. The method also can deliver a polypeptide to the lysosomes of CNS cells.

Abstract: This disclosure provides lentiviral vectors containing an attachment incompetent fusogenic polypeptide and a heterologous targeting polypeptide. Also provided are lentiviral packaging constructs, lentiviral packaging systems, and lentiviral gene delivery systems. Finally, methods of transducing a cell and methods of targeting a gene to a cell or tissue using the disclosed lentiviral vectors and systems are also provided.

Abstract: The present invention provides inducible gene transfer systems and gene transfer vectors for the safe and effective transfer and expression of genes in mammalian cells, and for a very high level of control of expression of the transferred genes. The inducible gene transfer systems of the present invention may be lentiviral vectors comprising a self-inactivating 5′ LTR, a modulator-responsive promoter, a nuclear import signal, a promoter operatively associated with a nucleic acid encoding a modulator-responsive receptor, an RNA stabilizing element, and a self-inactivating 3′ LTR. Thus, the present invention provides vectors for packaging and delivering DNA to both dividing and non-dividing cells. The present invention also provides methods for treating subjects with the gene transfer systems of the present invention, and cells containing the gene transfer systems.

Abstract: The invention provides a lentiviral vector capable of inhibiting the expression of at least one target gene. A lentiviral vector of the invention encompasses a first nucleic acid sequence derived from a target gene transcript and a second nucleic acid sequence corresponding to the reverse complement of said first nucleic acid sequence. A lentiviral vector of the invention capable of inhibiting the expression of a target gene is useful in therapeutic applications to inactivate disease-associated transcripts and thereby reduce the severity of inherited metabolic, infectious or malignant conditions. Methods for inhibiting one or more target genes in a cell as well as methods for producing a non-human mammal in which the expression of one or more target genes is inhibited also are provided by the present invention.

Abstract: A substantially purified lifeguard (LFG) polypeptide is provided. The polypeptide includes an amino acid sequence as set forth in SEQ ID NO: 2, or a conservative variant thereof. An isolated polynucleotide is provided that encodes an amino acid sequence as set forth in SEQ ID NO: 2, or a conservative variant thereof. An antibody is provided that binds to a polypeptide having an amino acid sequence as set forth in SEQ ID NO: 2. A method is provided for identifying a compound which affects a function of a polypeptide as set forth in SEQ ID NO: 2, or a conservative variant thereof, or affects the expression of a polynucleotide comprising a sequence as set forth in SEQ ID NO: 1. A method is provided for treating a subject with a disorder associated with decreased or increased Fas-mediated cell death. A method is provided for treating a patient having or at risk of having a disorder associated with increased Fas-mediated cell death.

Abstract: A substantially purified lifeguard (LFG) polypeptide is provided. The polypeptide includes an amino acid sequence as set forth in SEQ ID NO:2, or a conservative variant thereof. An isolated polynucleotide is provided that encodes an amino acid sequence as set forth in SEQ ID NO:2, or a conservative variant thereof. An antibody is provided that binds to a polypeptide having an amino acid sequence as set forth in SEQ ID NO:2. A method is provided for identifying a compound which affects a function a polypeptide as set forth in SEQ ID NO:2, or a conservative variant thereof, or affects the expression of a polynucleotide comprising a sequence as set forth in SEQ ID NO:1. A method is provided for treating a subject with a disorder associated with decreased or increased Fas-mediated cell death. A method is provided for treating a patient having or at risk of having a disorder associated with increased Fas-mediated cell death.

Abstract: In accordance with the present invention, there is provided a novel analytical method for identifying compounds which induce and/or inhibit signal transduction in cells. The invention method enables rapid testing of a variety of compounds to determine if they exert an influence on signal transduction. The invention assay can be carried out using unmodified cells and/or cell lines, avoiding the need for extensive preparation prior to analysis.

Abstract: The present invention provides packaging cell lines and recombinant lentiviral or retroviral particles produced therefrom, particularly pseudotyped retroviral particles. The packaging cell lines of the invention are produced by inducibly expressing an envelope protein by methods described herein. Also described is a screening assay for compounds that affect integration of viral nucleic acid into target (e.g., host) nucleic acid. Such compounds are identified based on their effect on viral integrase.

Abstract: The present invention provides packaging cell lines and recombinant lentiviral or retroviral particles produced therefrom, particularly pseudotyped retroviral particles. The packaging cell lines of the invention are produced by inducibly expressing an envelope protein by methods described herein. Also described is a screening assay for compounds that affect integration of viral nucleic acid into target (e.g., host) nucleic acid. Such compounds are identified based on their effect on viral integrase.

Abstract: The present invention provides a transrepressing protein of the Fos proto-oncogene family. The protein, FosB2, is characterized by having a leucine zipper domain and forming a heterodimer with a Jun related protein. This heterodimer is capable of binding to an AP-1 site and suppressing transcriptional transactivation of a promoter containing the AP-1 site.

Abstract: The present invention provides polynucleotide and polypeptide sequences for a trans-repressing protein of the Fos proto-oncogene family, where the polypeptide is characterized by having a leucine zipper domain and forming a heterodimer with a Jun related protein. This heterodimer is capable of biding to an AP-1 site and suppressing transcriptional transactivation of a promoter containing the AP-1 site.