Formation of location-specific, higher-order signaling complexes, now called supramolecular organizing centers (SMOCs), is an almost universal feature of innate immune signaling. SMOC-mediated signal transduction is distinct from classical signal transduction, in which a chain reaction of ligand-induced conformational changes, enzyme activation and second messenger production leads to signal transmission and amplification. SMOCs illustrate important principles involving cooperativity, signal amplification, threshold behavior and time delay of response, as well as proximity-driven allosteric enzyme activation, spatial and temporal control of activation and termination, and reduction of biological noise. These key signaling concepts are at the forefront of modern signal transduction theory, and understanding them at a rigorous molecular, structural and cell biological level would transform how we approach innate immunity, at both basic and applied levels. In this Pioneer Application, we will investigate a subset of these concepts that directly guide the development of attractive new models for targeted drug discovery, using fresh ideas and methodologies. Innate immunity is critically important for host-defense and inflammation, and its dysregulation underlies many human diseases, including genetic disorders, gout, psoriasis, lupus, multiple sclerosis, neurodegenerative diseases, diabetes, ulcerative colitis and Crohn's disease, just to name a few. We propose that SMOCs provide a previously untapped druggable proteome as they offer opportunities for dominant negative, rather than competitive inhibition as a result of the cooperativity in their assembly. These target sites may include polymerization interfaces on the oligomerization domains, SMOC-induced, intrinsically weak interactions required for allosteric enzyme activation, and potential SMOC-cytoskeleton interactions required for SMOC formation in cells. The principles learned from these stud

Public Health Relevance

Innate immunity offers the first line of defense against infection and other types of dangers. Innate immune receptors consist of pattern recognition receptors (PRRs) that sense conserved pathogen- or danger-associated molecular patterns (PAMPs or DAMPs), such as cell surface and endosomal Toll-like receptors (TLRs), and cytosolic Nod-like receptors (NLRs) and AIM2-like receptors (ALRs) that form inflammasomes. They also include a number of cytokine receptors that are the main executors of innate immunity such as those in the TNF receptor superfamily and the IL-1 receptor family. These receptors collectively elicit inflammatory, cell death and interferon responses to fight infection and restore homeostasis. However, abundant data suggest that many human diseases are caused or exacerbated by genetic alterations or dysregulation of innate immune pathways. These include genetic disorders, gout, psoriasis, lupus, multiple sclerosis, neurodegenerative diseases, diabetes, ulcerative colitis and Crohn's disease, just to name a few. Thus, these signaling processes constitute extremely compelling therapeutic targets for improving human health.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1HD087988-02
Application #
9137518
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Taylor-Zapata, Perdita
Project Start
2015-09-30
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
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