The present invention provides novel compositions and methods based on the discovery of the mechanisms and gene expression programs associated with homeostatic ILC2s and proinflammatory ILC2s that drive tissue inflammation. Immune signaling abnormalities in the small intestine can trigger chronic type 2 inflammation. Applicants analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA-seq at steady state and after induction of a type 2 inflammatory reaction to ovalbumin. Cell type composition and cell programs shifted in response to inflammation, especially in ILC2s. A key transcript in the inflammation-induced program in intestinal KLRG1+ILC2s was exon 5 of Calca, encoding the alpha-calcitonin gene-related peptide (a-CGRP). a-CGRP antagonized IL-25-induced activation of intestinal ILC2s and reduced their frequency in an ovalbumin reaction model. α-CGRP activated a cAMP response, which suppressed ILC2 proliferation. In homeostasis, α-CGRP was expressed by two subsets of ChAT+ enteric neurons, and genetic perturbation of α-CGRP increased the proportion of intestinal ILC2s and of Tuft cells. The results demonstrate that a-CGRP-mediated neuronal signaling suppresses ILC2 expansion and maintains type 2 immunity homeostasis.

The disclosure provides methods for treating vulvovaginal atrophy (VVA) and osteoporosis in breast cancer survivors and survivors of other malignancies with an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The disclosure provides methods for treating vulvovaginal atrophy (VVA) and osteoporosis in breast cancer survivors and survivors of other malignancies with an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

In certain embodiments osteoadsorptive fluorogenic substrates of cathepsin K (or other proteases) are provided. Utilizing a bisphosphonate targeting moiety, the fluorogenic substrates provide effective bone-targeted protease sensor(s). In certain embodiments the “probes” comprise cleavable fluorophore-quencher pair linked by a cathepsin K (or other protease) peptide substrate and tethered to a bisphosphonate. Unlike existing probes that are cleared within a few days in vivo, the probes described herein (e.g., OFS-1) allow for monitoring resorption over the course of longer time periods with a single dose.

In certain embodiments osteoadsorptive fluorogenic substrates of cathepsin K (or other proteases) are provided. Utilizing a bisphosphonate targeting moiety, the fluorogenic substrates provide effective bone-targeted protease sensor(s). In certain embodiments the “probes” comprise cleavable fluorophore-quencher pair linked by a cathepsin K (or other protease) peptide substrate and tethered to a bisphosphonate. Unlike existing probes that are cleared within a few days in vivo, the probes described herein (e.g., OFS-1) allow for monitoring resorption over the course of longer time periods with a single dose.

Disclosed herein are methods, devices, and systems for treating lens protein aggregation diseases by reducing the formation of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure. Specifically disclosed herein are ophthalmologic compositions comprising one or more agents that regulate water, sodium, and/or calcium ion transport and/or storage through lens fiber cell channels, and/or reduce the formation and/or production of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure.

Disclosed herein are methods, devices, and systems for treating lens protein aggregation diseases by reducing the formation of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure. Specifically disclosed herein are ophthalmologic compositions comprising one or more agents that regulate water, sodium, and/or calcium ion transport and/or storage through lens fiber cell channels, and/or reduce the formation and/or production of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure.

Disclosed herein are methods, devices, and systems for treating lens protein aggregation diseases by reducing the formation of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure. Specifically disclosed herein are ophthalmologic compositions comprising one or more agents that regulate water, sodium, and/or calcium ion transport and/or storage through lens fiber cell channels, and/or reduce the formation and/or production of proteins responsible for crowding, compacting, and/or causing increased internal lens pressure.

A method for treating, remedying, or preventing inflammatory skin disorders by administering a therapeutically effective dose of at least one an antagonist of a calcitonin gene-related peptide receptor in a pharmaceutically acceptable formulation. The method for treating, remedying, or preventing an inflammatory skin disorder by administering topically and to the pre-psoriatic rim a therapeutically effective dose of at least one an antagonist of a calcitonin gene-related peptide receptor in a pharmaceutically acceptable formulation.

A method for treating, remedying, or preventing inflammatory skin disorders by administering a therapeutically effective dose of at least one an antagonist of a calcitonin gene-related peptide receptor in a pharmaceutically acceptable formulation. The method for treating, remedying, or preventing an inflammatory skin disorder by administering topically and to the pre-psoriatic rim a therapeutically effective dose of at least one an antagonist of a calcitonin gene-related peptide receptor in a pharmaceutically acceptable formulation.