Pain management research from the NIH HEAL Initiative.

This article presents an overview of the pain research programs within the National Institutes of Health (NIH) Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®. Launched in 2018 to address the opioid crisis, the NIH HEAL Initiative supports research on addiction prevention and treatment. A key component of addiction prevention is the development of new, effective, non-addictive treatments for acute and chronic pain.

The Partnership for Accelerating Cancer Therapies.

As a part of the Cancer Moonshot, the National Cancer Institute, part of the National Institutes of Health, the Foundation for National Institutes of Health, the US Food and Drug Administration, and 12 pharmaceutical companies have formed a 5-year, $220 million precompetitive public-private research collaboration called the Partnership for Accelerating Cancer Therapies. A systematic cross-sector effort to identify and develop robust, standardized biomarkers and related clinical data, Partnership for Accelerating Cancer Therapies will support the selection and testing of promising immunotherapies for the treatment of cancer, with the goal of bringing effective therapy to more patients.

SLP-76 is required for optimal CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow.

Rapid arrest of T cells at target sites upon engagement of chemokine receptors is crucial to the proper functioning of the immune system. Although T-cell arrest always occurs under hydrodynamic forces in vivo, most studies investigating the molecular mechanisms of arrest have been performed under static conditions. While the requirement of the adapter protein SLP-76 (Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa) in TCR-induced integrin activation has been demonstrated, its role in chemokine-triggered T-cell adhesion is unknown.

NF-κB, inflammation, and metabolic disease.

Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.

Independent and cooperative roles of adaptor molecules in proximal signaling during FcepsilonRI-mediated mast cell activation.

Activation through FcepsilonRI, a high-affinity IgE-binding receptor, is critical for mast cell function during allergy. The formation of a multimolecular proximal signaling complex nucleated by the adaptor molecules SLP-76 and LAT1 is required for activation through this receptor. Based on previous T-cell studies, current dogma dictates that LAT1 is required for plasma membrane recruitment and function of SLP-76.

Cutting edge: rescue of pre-TCR but not mature TCR signaling in mice expressing membrane-targeted SLP-76.

SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) organizes signaling from immunoreceptors, including the platelet collagen receptor, the pre-TCR, and the TCR, and is required for T cell development. In this study we examine a mouse in which wild-type SLP-76 is replaced with a mutant constitutively targeted to the cell membrane. Membrane-targeted SLP-76 (MTS) supports ITAM signaling in platelets and from the pre-TCR.

Regulation of T cell integrin function by adapter proteins.

Integrins are cell surface heterodimers that bind adhesion molecules expressed on other cells or in the extracellular matrix. Integrin-mediated interactions are critical for T cell development in the thymus, migration of T cells in the periphery, and induction of T cell effector functions. In resting T cells, integrins are maintained in a low affinity state.

Indirect involvement of allergen-captured mast cells in antigen presentation.

It is generally thought that mast cells influence T-cell activation nonspecifically through the release of inflammatory mediators. In this report, we provide evidence that mast cells may also affect antigen-specific T-cell responses by internalizing immunoglobulin E-bound antigens for presentation to antigen-specific T cells. Surprisingly, T-cell activation did not require that mast cells express major histocompatibility complex class II, indicating that mast cells were not involved in the direct presentation of the internalized antigens.