A5080087574- Pain Mechanisms and Treatments
- Axon Guidance and Neuronal Signaling
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Hereditary Neurological Disorders
- Neuropeptides and Animal Physiology
- Pain Management and Placebo Effect
- Nicotinic Acetylcholine Receptors Study
- Atherosclerosis and Cardiovascular Diseases
- Vagus Nerve Stimulation Research
- Neurofibromatosis and Schwannoma Cases
- Anesthesia and Neurotoxicity Research
- Angiogenesis and VEGF in Cancer
- Cancer, Stress, Anesthesia, and Immune Response
- Neuroscience and Neural Engineering
- Venomous Animal Envenomation and Studies
- Cell Adhesion Molecules Research
- Protein Kinase Regulation and GTPase Signaling
- Peripheral Neuropathies and Disorders
- Phytochemistry and Biological Activities
- Chemical synthesis and alkaloids
- Plant-based Medicinal Research
- Autoimmune Neurological Disorders and Treatments
- Pharmacological Receptor Mechanisms and Effects
- Alkaloids: synthesis and pharmacology
University of Arizona
2016-2024
Indiana University – Purdue University Indianapolis
2017
Indiana University School of Medicine
2017
University of Virginia
2004
Abstract Global spread of severe acute respiratory syndrome coronavirus 2 continues unabated. Binding 2's spike protein to host angiotensin-converting enzyme triggers viral entry, but other proteins may participate, including the neuropilin-1 receptor (NRP-1). Because both and vascular endothelial growth factor-A (VEGF-A)—a pronociceptive angiogenic factor, bind NRP-1, we tested whether could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuron firing was blocked by NRP-1 inhibitor...
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice haploinsufficiency have been instructive in identifying sensitization ion channels as possible cause underlying heightened pain suffered by patients NF1. However, behavioral assessments led uncertain conclusions about potential causal role We used clustered regularly interspaced short palindromic repeats...
Protein-protein interaction inhibitor of the sodium NaV1.7 channel has analgesic effects in preclinical models pain.
Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na
Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in expression collapsin response mediator protein 2 (CRMP2), cytosolic reported regulate trafficking activity presynaptic N-type voltage-gated calcium (Cav2.2) channels. Because neurofibromin, product binds inhibits CRMP2,...
Abstract The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden chronic pain faced by >100 million Americans. Motivated this challenge, natural product extracts library was screened identified plant extract that targets activity voltage-gated calcium channels. This profile is interest potential treatment for neuropathic pain. active derived from desert...
N-type voltage-gated calcium (Cav 2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav 2.2 channel antagonists recommended as first-line treatment for pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets to the sensory neuron membrane allosterically modulates their...
Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors channels. The dysregulation trafficking voltage-gated ion channels is an emerging mechanism in the etiology neuropathic pain. We identify phosphorylation collapsin response mediator protein 2 (CRMP2), a reported regulate presynaptic calcium sodium A spared injury (SNI) expression cyclin dependent kinase 5 (Cdk5)-phosphorylated form...
Abstract Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 are composed α, β, γ and α2δ subunits. The β subunits CaV cytoplasmic proteins that increase the surface expression pore-forming α subunit CaV. We targeted high-affinity protein–protein interface CaVβ's pocket within CaVα subunit. Structure-based virtual screening 50,000 small molecule library docked to led identification...
No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance on prescription opioids pain despite their poor ability to improve function has led national opioid crisis. In 2018, NIH launched Helping End Addiction Long-term plan spur discovery and validation novel targets mechanisms develop alternative nonaddictive treatment options. Phytochemicals with medicinal properties have long been used various treatments worldwide....
Abstract Pharmacological ablation of rostral ventromedial medulla (RVM) mu opioid receptor–expressing cells before peripheral nerve injury prevents the development neuropathic pain. However, whether these neurons are required for expression established pain is not known. Male Oprm1 Cre heterozygous (MOR ) or wild-type WT mice received AAV8-hSyn-DIO-hM4D(Gi)-mCherry in RVM. After partial sciatic ligation (PSNL), we evaluated behaviors and descending control nociception response to acute...
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well bone, nerve and muscle constitution. Peripheral neuropathy NF1 constitutes potentially severe clinical complication associated with increased morbidity mortality. The discovery effective therapies for pain depends on mechanistic understanding that has been limited, part, by relative lack availability animal...
For an affliction that debilitates estimated 50 million adults in the United States, current chronic pain management approaches are inadequate. The Centers for Disease Control and Prevention have called a minimization opioid prescription use conditions, thus, it is imperative to discover alternative non-opioid based strategies. realization of this call, library natural products was screened search pharmacological inhibitors both voltage-gated calcium channels sodium channels, which excellent...
Abstract Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an the CV2/collapsin mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related...
Endothelial cells line the inner wall of blood vessels and play an important role in regulation vascular tone, permeability, new formation. cell dysfunction is implicated development progression many cardiovascular diseases including ischemic heart disease. To examine function characterization coronary endothelial cells, isolation first step it requires high purity quantity to conduct subsequent experiments. This protocol describes efficient method isolate adult mouse cells. The dissected...
Ca 2+ ‐sensitization of smooth muscle occurs through inhibition myosin light chain phosphatase (MLCP) leading to an increase in the MLCK:MLCP activity ratio. MLCP is inhibited phosphorylation its regulatory subunit (MYPT‐1) following activation RhoA/Rho kinase (ROK) pathway or PP1c inhibitory protein, CPI‐17, by PKC δ ROK. Here, we explore crosstalk between these two modes a natural CPI‐17 knockout, chicken amnion. GTPγS elicited ‐sensitized force which was relaxed GDI Y‐27632, however,...
The voltage-gated calcium channels CaV3.1-3.3 constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. unique properties of low-voltage-activation, faster inactivation, slower deactivation these support their role in modulation cellular excitability low-threshold firing. Thus, selective channel antagonists highly sought after. Here, we explored Ugi-azide multicomponent reaction products to identify compounds targeting channel....
Abstract Vascular endothelial growth factor A (VEGF-A) is a pronociceptive that causes neuronal sensitization and pain. We reported blocking the interaction between membrane receptor neuropilin 1 (NRP1) VEGF-A–blocked VEGF-A–mediated sensory neuron hyperexcitability reduced mechanical hypersensitivity in rodent chronic neuropathic pain model. These findings identified NRP1-VEGF-A signaling axis for therapeutic targeting of In an in-silico screening approximately 480 K small molecules binding...
Abstract Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding SARS-CoV-2’s Spike protein to host angiotensin converting enzyme triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both and vascular endothelial growth factor-A (VEGF-A) – a pro-nociceptive angiogenic factor, bind NRP-1, we tested if could block VEGF-A/NRP-1 signaling. VEGF-A–triggered sensory neuronal firing was blocked by...
Endothelial cells line the inner wall of blood vessels and play an important role in regulation vascular tone, permeability, new formation. cell dysfunction is implicated development progression many cardiovascular diseases including ischemic heart disease. To examine function characterization coronary endothelial cells, isolation first step it requires high purity quantity to conduct subsequent experiments. This protocol describes efficient method isolate adult mouse cells. The dissected...
Abstract Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, injury. The number persons experiencing this type is substantial, affecting upwards 50 million adults in United States. Pharmacotherapy most severe chronic patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective up to two-thirds population although opioids initially effective, their long-term use associated...
Abstract Despite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition a ubiquitin-like modifier (SUMO) on NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered 15 amino acid CRMP2 regulatory sequence (CRS) unique to is essential for this coupling. preferentially bound...