University of Massachusetts

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

Michael P Czech

Adilson L Guilherme

Aimee Powelka

Andrew D Cherniack

Silvia Corvera

Myriam Aouadi

Xiaoqing Tang

Jes K Klarlund

Gary R Ostroff

George Kunos

Mengxi Wang

Yuefei Shen

Rachel Roth Flach

Tony Jourdan

Emmanouela Tsagkaraki

Sarah M Nicoloro

Provided herein are methods and compositions for disrupting expression of nuclear receptor interacting protein 1 (Nrip1) in adipose cells, and methods of use of such adipose cells for treating, or reducing risk of, a condition associated with an elevated body mass index (BMI).

Targeting Nrip1 to alleviate metabolic disease

Complexes comprising a nucleic acid-guided endonuclease, a sequence-specific targeting nucleic acid and an amphipathic helical peptide are provided. Compositions and methods for delivery of complexes comprising a nucleic acid-guided endonuclease, a sequence-specific targeting nucleic acid and an amphipathic helical peptide to mammals for both research and therapeutic use are provided. Methods of treating or reducing one or more symptoms of type 2 diabetes, prediabetes and/or gestational diabetes are provided.

Complexes for gene deletion and editing

Compositions comprising glucan-encapsulated siRNA directed against a region of the gene encoding the human CB1 receptor for use in the treatment of type 2 diabetes mellitus in a human subject. Additionally, methods for treating type 2 diabetes mellitus in a subject, comprising administering to the subject a composition comprising glucan-encapsulated siRNA directed against the CB1 receptor.

Glucan-encapsulated siRNA for treating type 2 diabetes mellitus

Provided herein are methods of inducing differentiation of a mammalian myoblast into a mammalian myocyte that include contacting a mammalian myoblast with an oligonucleotide that decreases Mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) mRNA expression in a mammalian myoblast or myocyte. Also provided are methods of inducing mammalian myoblasts or myocytes to form a myotube that include contacting two or more mammalian myoblasts or two or more mammalian myocytes with an oligonucleotide that decreases Map4k4 mRNA expression in a mammalian myoblast or myocyte. Also provided are methods of identifying a candidate agent useful for inducing muscle formation, and compositions containing an oligonucleotide that decreases Map4k4 mRNA expression in mammalian myoblast or myocyte and one or more additional muscle therapeutic agents and/or muscle-building neutraceuticals.

Compositions and methods for inducing myoblast differentiation and myotube formation

Provided herein are methods of decreasing leukocyte extravasation from a lymph or blood vessel into a tissue in a mammal, methods of decreasing fluid leakage from a lymph or blood vessel in a mammal in need thereof, methods of decreasing formation of atherosclerotic plaques in a mammal in need thereof, and methods of treating atherosclerosis in a mammal that include administering to the mammal an oligonucleotide that decreases Mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) mRNA expression in an endothelial cell. Also provided are methods of identifying a candidate agent useful for decreasing leukocyte extravasation or decreasing fluid leakage from a lymph or blood vessel in a mammal, and compositions containing an oligonucleotide that decreases Map4k4 mRNA expression in an endothelial cell and additional therapeutic agents.

Compositions and methods for decreasing leukocyte extravasation and vessel fluid leakage

Inhibition of RIP140 increases glucose transport. Compounds that inhibit RIP140 expression or activity are useful for treating disorders associated with aberrant glucose transport (e.g., diabetes), treating obesity, increasing metabolism (e.g., fatty acid metabolism), and increasing brown fat.

RIP140 regulation of glucose transport

Methods and compositions for delivering agents (e.g., gene silencing agents) and molecules to cells using yeast cell wall particles are presented herein. Embodiments of the invention are particularly useful for the delivery of nucleic acids (e.g., siRNAs) to cells.

Encapsulated nanoparticles for nucleic acid delivery

Methods and compositions for modulating glucose transport are provided herein.

Increasing glucose transport and insulin-stimulated glucose uptake

RIP140 regulation of diabetes

Glucose-transport related genes, polypeptides, and methods of use thereof

The present invention relates to the discovery of a novel isoform of phosphatidylinositide binding protein, referred to herein a &ldquo;general receptors for phosphoinositides&rdquo; or &ldquo;GRPs&rdquo;. The GRP molecules show a modular structure comprising a domain homologous to the yeast SEC7 gene product and a pleckstrin homology (PH) domain. GRP proteins exhibit specific high affinity binding to products of the lipid kinase phosphatidylinositol-3-OH kinase, such as phosphotidylinositol-3,4,5. As described herein, GRP proteins may function as adaptors between membrane signalling and multiple downstream targets. Thus, GRP polypeptides potentially mediate multiple signalling events such as cell adhesion and membrane trafficking, among others. This invention describes isolated and antisense nucleic acids molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals in which GRP gene has been introduced or disrupted. In addition, the invention provides isolated GRP proteins, fusion proteins, antigenic peptides and anti-GRP antibodies. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided. The invention further provides a method of cloning novel phosphatidylinositol binding protein.

General receptors for phosphoinositides and uses related thereto

Novel phosphatidylinositide binding proteins, referred to herein a &ldquo;general receptors for phosphoinositides&rdquo; or &ldquo;GRPs&rdquo; are disclosed which are useful as adaptors between membrane signalling and multiple downstream targets. This invention describes isolated and antisense nucleic acids molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals in which GRP gene has been introduced or disrupted. In addition, the invention provides isolated GRP proteins, fusion proteins, antigenic peptides and anti-GRP antibodies. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided. The invention further provides a method of cloning novel phosphatidylinositol binding proteins.

Binding proteins for phosphoinositides, GRP1 or general receptor 1 for phophoinositide

The invention discloses a chimeric GLUT transporter including a GLUT receptor polypeptide fused to a domain of a detectable heterologous polypeptide and cells expressing such reporter constructs. Cells expressing a detectably-tagged chimeric GLUT transporter are used in methods of screening candidate compounds for their ability to agonize or antagonize an interaction between a ligand and a receptor, e.g., insulin. In addition, a 30 amino acid intracellular retention sequence is disclosed.

Growing community of inventors

Westborough, MA, United States of America

Michael P Czech