Vitamin B5 is a context-dependent dietary regulator of nociception.

Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies.

PGC1α Controls Sucrose Taste Sensitization in Drosophila.

Perceived palatability of food controls caloric intake. Sweet taste is the primary means of detecting the carbohydrate content of food. Surprisingly, sweet taste sensitivity is responsive to extrinsic factors like diet, and this occurs by unknown mechanisms.

Systematic functional identification of cancer multi-drug resistance genes.

Background: Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs.

Results: In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways.

Peripheral (α2δ Ca channel subunit) expression is required for neuropathic sensitization in .

Nerve injury leads to devastating and often untreatable neuropathic pain. While acute noxious sensation (nociception) is a crucial survival mechanism and is conserved across phyla, chronic neuropathic pain is considered a maladaptive response owing to its devastating impact on a patient's quality of life. We have recently shown that a neuropathic pain-like response occurs in adult .

Nerve injury drives a heightened state of vigilance and neuropathic sensitization in .

Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects.

Neuronal regulates motor circuit integrity and controls motor function and lifespan.

Neuronal aging involves a progressive decline in cognitive abilities and loss of motor function. Mutations in human genes () lead to a wide-range of diseases including muscular dystrophy, peripheral neuropathy and progeria. Here we investigate the role of neuronal in regulating age-related phenotypes.

Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote.

The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis.

A fruit fly model for studying paclitaxel-induced peripheral neuropathy and hyperalgesia.

: Paclitaxel-induced peripheral neuropathy is a common and limiting side effect of an approved and effective chemotherapeutic agent. The cause of this nociception is still unknown. : To uncover the mechanism involved in paclitaxel-induced pain, we developed a thermal nociceptive model to show the effects of paclitaxel exposure on third instar larvae.

A simple high throughput assay to evaluate water consumption in the fruit fly.

Water intake is essential for survival and thus under strong regulation. Here, we describe a simple high throughput system to monitor water intake over time in Drosophila. The design of the assay involves dehydrating fly food and then adding water back separately so flies either eat or drink.

Epiregulin and EGFR interactions are involved in pain processing.

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing.

Sucralose Promotes Food Intake through NPY and a Neuronal Fasting Response.

Non-nutritive sweeteners like sucralose are consumed by billions of people. While animal and human studies have demonstrated a link between synthetic sweetener consumption and metabolic dysregulation, the mechanisms responsible remain unknown. Here we use a diet supplemented with sucralose to investigate the long-term effects of sweet/energy imbalance.

Fruit flies as a powerful model to drive or validate pain genomics efforts.

Chronic pain is a disabling condition that persists even after normal healing processes are complete and presents considerable physical, psychological and financial burdens for patients globally. However, current analgesic treatments do not meet clinical needs. Here, we review genomic and pharmacogenomic studies of pain in humans and nociception in the fruit fly Drosophila melanogaster, and provide evidence supporting the use of fly genetics to compliment genome-wide and pharmacogenomic studies of human conditions, such as pain.

Conserved systems and functional genomic assessment of nociception.

Chronic pain represents a significant public health concern and current therapies do not adequately meet patient needs. With the advent of genomic technologies, pain researchers have begun to identify key loci associating with human pain diseases, and these data are instructing the development of next generation analgesics. Although human genetics efforts have been effective, complementary approaches, including functional genomics, may provide additional insight into pain genetics and help identify additional new drug targets.

Synaptic PI(3,4,5)P3 is required for Syntaxin1A clustering and neurotransmitter release.

PI(3,4,5)P3 is a low-abundance lipid thought to play a role in the regulation of synaptic activity; however, the mechanism remains obscure. We have constructed novel split Venus-based probes and used superresolution imaging to localize PI(3,4,5)P3 at Drosophila larval neuromuscular synapses. We find the lipid in membrane domains at neurotransmitter release sites, where it concentrates with Syntaxin1A, a protein essential for vesicle fusion.

Phosphoinositides at the neuromuscular junction of Drosophila melanogaster: a genetic approach.

Phosphoinositides are critically important for numerous cellular signaling pathways such as membrane trafficking, cytoskeleton rearrangement, and ion channel regulation in eukaryotic organisms. The physiological relevance of phosphoinositide metabolism at the Drosophila neuromuscular junction (NMJ) has been illustrated using several mutants that lack crucial factors of phosphoinositide signaling. Although several decades of research in both in vitro and in vivo models have led to an understanding of the mechanisms of lipid-protein interactions and downstream signaling, the details on how their temporal and spatial distribution is regulated at the sub-cellular level in vivo remains poorly understood.

WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling.

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)] is a membrane lipid involved in several signaling pathways. However, the role of this lipid in the regulation of synapse growth is ill-defined. Here we identify PI(4,5)P(2) as a gatekeeper of neuromuscular junction (NMJ) size.