Identification and Characterisation of Novel Positive Allosteric Modulators of the Galanin 2 Receptor
Poster Oct 10, 2014
Chronic nerve damage or injury induces alterations in the primary sensory neurons in the dorsal root ganglion (DRG) and their central connections. This leads to the development of spontaneous pain; allodynia (the perception of pain from a normally innocuous stimulus), hyperalgesia (an exaggerated response to any given pain stimulus), and expansion of the receptive pain field. These functional changes can result in the development of chronic neuropathic pain (NP), the most common causes of which are diabetes, alcoholism, and chemotherapy for cancer/HIV.
The physiological effects of galanin are mediated by activation of galanin receptors (GalR1, GalR2 and GalR3) which inhibit adenylyl cyclase. GalR2 in addition, mediates intracellular calcium mobilisation. High levels of endogenous galanin in injured primary afferent neurons activate peripheral GalR2 and leads to a marked reduction in nociceptive responses. Positive allosteric modulators (PAMs) of GalR2 could afford therapeutic advantage including, improved receptor selectivity, retention of physiologically-controlled spatial and temporal response, and self-limiting saturability of effect.
We have configured a functional HTRF IP-1 detection assay (Cisbio) which we used to screen a 100K subset of the MRCT compound library to identify novel activators of the GalR2 receptor. Using CHO cells stably expressing GalR2, inclusion of a submaximal concentration (EC30) of galanin facilitated simultaneous detection of both PAMs and agonists. We will show data relating to assay performance and hit rates, in addition to secondary studies for the deconvolution of agonists and PAMs. We will present hit characterisation of putative PAMs and their analogues.
Regulatory T-Cells (Tregs) Within Bone Marrow-Derived Stem Cells (BMSCs) Actively Confer Immunomodulatory and Neuroprotective Effects Against StrokePoster
We found a distinct subpopulation of Tregs within BMSCs. Tregs and BMSCs in co-culture conferred neuroprotection that varied in a dose-dependent manner. Tregs minimized stem cell production of IL-6, a pro-inflammatory cytokine, and inhibited BMSC secretion of FGF-beta, a cytokine related to BMSC proliferation and differentiation. The ratio of Tregs found natively in BMSCs is optimally adapted to provide the maximum neuroprotective benefit of stem cell treatment after ischemic stroke.READ MORE
Internet-Based Biomarker Collection Feasibility: Experiences of a Tobacco Cessation Program for People Living with HIVPoster
This project introduces video-conferencing as a method for biomarker collection in research and will explain how biomarker collection via video-conferencing was implemented in a pilot ehealth intervention.READ MORE
Alterations in Immunophenotype of Autoimmune-prone Hypomorphic RAG-deficient Patients with CID-G/AI PhenotypePoster
Patients with partial deficiency of recombination-activating genes 1 or 2 (RAG1/2) can present with a wide spectrum of primary immunodeficiencies including combined immunodeficiency with granuloma and/or autoimmunity (CID-G/AI). Prior case reports have highlighted alterations in B and T cell compartments; however comprehensive characterization of these cell populations with focus on autoreactive-prone subsets has not been reported.READ MORE