A5072138284- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Diabetes Management and Research
- Metabolism, Diabetes, and Cancer
- Cardiac electrophysiology and arrhythmias
- Neuroscience and Neural Engineering
- Diabetes and associated disorders
- Photoreceptor and optogenetics research
- Memory and Neural Mechanisms
- Ion Channels and Receptors
- Genetics and Neurodevelopmental Disorders
- Autism Spectrum Disorder Research
- Neurogenesis and neuroplasticity mechanisms
- Neuroscience of respiration and sleep
- Epilepsy research and treatment
- Folate and B Vitamins Research
- Neuropeptides and Animal Physiology
- Phosphodiesterase function and regulation
- Neurobiology and Insect Physiology Research
- Regulation of Appetite and Obesity
- Heart Failure Treatment and Management
- Protein Kinase Regulation and GTPase Signaling
Duke University
2013-2024
Duke-NUS Medical School
2019
Duke Medical Center
2008-2017
Duke University Hospital
2010-2017
Pediatrics and Genetics
2017
Tianjin Medical University
2012-2016
Hiroshima University
2003-2012
Amgen (United States)
2002-2011
Durham VA Medical Center
2010
Wayne State University
2006-2009
Specialized somatosensory neurons detect temperatures ranging from pleasantly cool or warm to burning hot and painful (nociceptive). The precise temperature ranges sensed by thermally sensitive is determined tissue-specific expression of ion channels the transient receptor potential (TRP) family. We show here that in Drosophila, TRPA1 required for sensing nociceptive heat. identify two previously unidentified protein isoforms dTRPA1, named dTRPA1-C dTRPA1-D, explain this requirement. A...
Hyperexcitable neurons in brain organoids Individuals with Angelman syndrome experience intellectual disability and seizures throughout their lives. In this condition, ubiquitin-mediated degradation of a key potassium channel is disrupted, allowing for the neuronal excitability network synchronization that leads to seizure. Sun et al. used organoid technology study what happens human mutation ubiquitin ligase implicated syndrome. these vitro models mouse model syndrome, antagonists...
Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied an acute increase insulin, enhances itself paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- fivefold InR1-G9 α cells and ∼18-fold perfused pancreata insulin-deficient...
We previously reported a new line of Shank3 mutant mice which led to complete loss by deleting exons 4-22 (Δe4-22) globally. Δe4-22 display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior excessive grooming, profound deficit in instrumental learning. However, the anatomical neural circuitry underlying these are unknown. generated with selectively deleted forebrain, striatum, striatal D1 D2 cells. These were used interrogate...
Activation of muscarinic cholinergic receptors on pyramidal cells the cerebral cortex induces appearance a slow afterdepolarization that can sustain autonomous spiking after brief excitatory stimulus. Accordingly, this phenomenon has been hypothesized to allow for transient storage memory traces in neuronal networks. Here we investigated molecular basis underlying receptor-induced using biological and electrophysiological strategies. We find ability induce inward aftercurrent is inhibited by...
Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for reducing excess hepatic glucose production in patients with type 2 diabetes. Despite extensive efforts, there is currently no human that directly inhibits glucagon/glucagon receptor pathway. We undertook a novel by generating high-affinity monoclonal antibodies (mAbs) to (GCGR) display potent antagonistic activity vitro and vivo. A single injection of lead antibody, mAb B, at 3 mg/kg, normalized...
Uncontrolled hepatic glucose output (HGO) contributes significantly to the pathological hyperglycemic state of patients with type 2 diabetes. Glucagon, through action on its receptor, stimulates HGO, thereby leading increased glycemia. Antagonizing glucagon signaling pathway represents an attractive therapeutic approach for treatment We previously reported generation and characterization several high-affinity monoclonal antibodies (mAbs) targeting receptor (GCGR). In present study, we...
In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing signalling improves function prevents adverse remodelling in failing heart. Glucagon's action on glucose lipid homeostasis counteract that of insulin's action. We hypothesised pharmacological antagonism myocardial glucagon action, using a human monoclonal antibody (mAb A) against receptor (GCGR), G-protein coupled receptor, will enhance sensitivity...
Targeted deletion of the gene encoding neuronal and neuroendocrine secreted polypeptide VGF (nonacronymic) produces a lean, hypermetabolic mouse. Consistent with this phenotype, mRNA levels are regulated in hypothalamic arcuate nucleus response to fasting. To gain insight into site(s) mechanism(s) action VGF, we further characterized expression hypothalamus. Double-label studies indicated that pro-opiomelanocortin were coexpressed lateral neurons fed state, was induced after fasting medial...
Fibroblast growth factor homologous factors (FHFs) are not factors, but instead bind to voltage-gated Na+ channels (NaV) and regulate their function. Mutations in FGF14, an FHF that is the locus for spinocerebellar ataxia 27 (SCA27), believed be pathogenic because of a dominant-negative reduction NaV currents cerebellar granule cells. Here, we demonstrate FGF14 also regulates members presynaptic CaV2 Ca2+ channel family. Knockdown cells reduced diminished vesicular recycling, marker influx....
Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na(+) (NaV) 'resurgent' current, which allows renewed influx during membrane repolarization. Resurgent current results from unbinding blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent have not been fully identified. In this study, we show the NaV auxiliary subunit FGF14 'b' isoform, locus for inherited spinocerebellar ataxias,...
Genetic defects in the synaptic scaffolding protein gene, SHANK2, are linked to a variety of neuropsychiatric disorders, including autism spectrum schizophrenia, intellectual disability, and bipolar disorder, but molecular mechanisms underlying pleotropic effects SHANK2 mutations poorly understood. We generated characterized line Shank2 mutant mice by deleting exon 24 (Δe24). Shank2Δe24-/- engage significantly increased locomotor activity, display abnormal reward-seeking behavior, anhedonic,...
Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na+ (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent current and accelerates across the family. Arrhythmia epilepsy mutations located in NaV1.5 NaV1.2 CTDs, respectively, reduce...
The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to efficacy and safety REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This randomized controlled which 21 patients with diabetes were enrolled. Glycaemic control insulin use evaluated outpatient inpatient settings, before after single 70-mg dose REMD-477 (half-life 7-10 days) or placebo. Inpatient 26% (95% CI, 47%, 4%) lower day dosing than placebo (P = .02). Continuous glucose...
The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in insulin-centric clinical environment. To investigate the metabolic effects type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody competitive antagonist receptor. As expected, 2.59 suppresses hepatic glucose production improves glycemia. Surprisingly, it also enhances insulin action both liver skeletal muscle, coinciding increase AMP-activated protein...
Significance Cardiovascular disease remains the leading cause of mortality in United States, and cardiac arrhythmia underlies majority these deaths. Here, we report a new mechanism for congenital human due to defects regulation primary Na v channel, 1.5 ( SCN5A ), by family signaling molecules termed fibroblast growth factor homologous factors (FHFs). Individuals harboring variants that affect 1.5/FHF interactions display atrial ventricular phenotypes, syncope, sudden death. The variant...
Summary: Purpose: The long‐lasting antiseizure effects of levetiracetam (LEV) have been observed in the spontaneously epileptic rat (SER) that expresses both tonic and absence‐like seizures. Furthermore, antiepileptogenic LEV addition to reported amygdala‐kindling model rats. This suggests seizure protection may be at least partly due its effects. Therefore this study aimed differentiate potential by administering continuously SERs before appearance any expression. Methods: was administered...
Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels glucagon-like peptide-1 (GLP-1). To investigate contribution GLP-1 to antidiabetic actions GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) wild-type mice and knockout (GLP-1R KO) mice. Treatment mAb B lowered fasting blood glucose, improved glucose tolerance, enhanced glucose-stimulated insulin secretion during intraperitoneal tolerance test (ipGTT). In contrast, treatment...