Abstract: Provided herein are engineered tuberous sclerosis complex 2 (TSC2) polypeptides in which the ability of a residue corresponding to a serine residue in a wild type TSC2 polypeptide to be phosphorylated is altered. In some cases, an engineered TSC2 polypeptide cannot be phosphorylated (e.g., by substituting a serine residue with an alanine residue). In some cases, an engineered TSC2 polypeptide can act as if it is constitutively phosphorylated (e.g., by substituting a serine residue with a glutamic acid residue). Also provided herein are engineered immune cells including altered TSC2 polypeptides or including nucleic acid sequences encoding altered TSC2 polypeptides, and methods of making and using such engineered immune cells.

Abstract: The disclosed in vitro systems allow for multiple organs (organoids) to be cultured in the same conditions, connected with the same microcirculation, subjected to the same pathological state, and treated with the same therapeutic approach. This allows for determination of the how various organ systems respond to a pathological stress and also how a therapeutic approach may effect various organoids differently. The in vitro systems also provide for single organoids.

Abstract: The disclosure is directed to methods for inhibiting toxic protein accumulation in cells by modulating the phosphorylation of carboxy terminus of heat shock cognate 70 interacting protein (CHIP), as well as a method for treating a disease caused by proteotoxicity in cells by increasing or inducing the activity of CHIP in a subject.

Abstract: Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.

Abstract: Provided herein are engineered tuberous sclerosis complex 2 (TSC2) polypeptides in which the ability of a residue corresponding to a serine residue in a wild type TSC2 polypeptide to be phosphorylated is altered. In some cases, an engineered TSC2 polypeptide cannot be phosphorylated (e.g., by substituting a serine residue with an alanine residue). In some cases, an engineered TSC2 polypeptide can act as if it is constitutively phosphorylated (e.g., by substituting a serine residue with a glutamic acid residue). Also provided herein are engineered immune cells including altered TSC2 polypeptides or including nucleic acid sequences encoding altered TSC2 polypeptides, and methods of making and using such engineered immune cells.

Abstract: Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.