A5010136511- Pain Mechanisms and Treatments
- Neurogenetic and Muscular Disorders Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Amyotrophic Lateral Sclerosis Research
- Neurobiology and Insect Physiology Research
- Olfactory and Sensory Function Studies
- Neuroscience and Neuropharmacology Research
- Biochemical Analysis and Sensing Techniques
- Parkinson's Disease Mechanisms and Treatments
- Ion channel regulation and function
- Neurogenesis and neuroplasticity mechanisms
- Neuropeptides and Animal Physiology
- Alzheimer's disease research and treatments
- Receptor Mechanisms and Signaling
- Cancer-related cognitive impairment studies
- Stress Responses and Cortisol
- CRISPR and Genetic Engineering
- Glioma Diagnosis and Treatment
- Brain Metastases and Treatment
- Ion Channels and Receptors
- Mitochondrial Function and Pathology
- Anesthesia and Neurotoxicity Research
- Traumatic Brain Injury and Neurovascular Disturbances
- Traumatic Brain Injury Research
- RNA regulation and disease
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2017-2025
National Institutes of Health
2014-2025
Eunice Kennedy Shriver Center
2023
Health and Human Development (2HD) Research Network
2019-2020
National Institute of Neurological Disorders and Stroke
2015-2016
Genentech
2013-2015
Columbia University
2007-2008
Amsterdam Nursing Home
2007
The senses of touch and proprioception evoke a range perceptions rely on the ability to detect transduce mechanical force. molecular neural mechanisms underlying these sensory functions remain poorly defined. stretch-gated ion channel PIEZO2 has been shown be essential for aspects mechanosensation in model organisms.We performed whole-exome sequencing analysis two patients who had unique neuromuscular skeletal symptoms, including progressive scoliosis, that did not conform standard...
LRRK2 autophosphorylation on Ser 1292 may be a useful indicator of kinase activity, providing readout for screening candidate inhibitors.
Abstract Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases mouse spinal cord have been published in recent years but not integrated together. Here, we generate an atlas types based on single-cell transcriptomic data, unifying available datasets into a common reference framework. We report hierarchical structure postnatal relationships, with location providing highest level organization, then neurotransmitter status, family, and finally,...
Abstract In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over past hundred years, yet full heterogeneity of these and their different functional roles adult remain to be defined. Here, we develop a targeted single nuclear RNA sequencing approach use it identify an array interneurons, visceral skeletal neurons. Our data expose markers for distinguishing classes rich diversity. Specifically, neurons, which provide autonomic...
The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding cellular diversity, characterizing human biology directly is important to uncover specialized features basic function pathology. Here, we present taxonomy the adult using single-nucleus RNA sequencing with spatial transcriptomics antibody validation. We identified 29 glial clusters 35 neuronal clusters, organized...
There is a high demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition LRRK2 activity potentially viable treatment option Parkinson's disease patients. Herein we disclose the use property structure-based drug design optimization highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation vitro-in correlations. Guided by...
Blocking dual leucine zipper kinase slows disease progression in animal models of ALS and Alzheimer’s disease.
The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, antibodies can block cell-to-cell spreading. Although mechanisms anti-tau function vivo are unknown, effector might promote microglia-mediated clearance. this study, we investigated whether antibody is required for targeting tau. We compared efficacy and vitro two versions the same antibody, without function, measuring pathology, neuron health, microglial function. Both reduced accumulation...
Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable assessing implications sustained vivo LRRK2 inhibition. Using previously reported aminopyrazole as lead molecule, were able to engineer structural modifications solvent-exposed region ATP-binding site that...
Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that extensively spliced, producing different isoforms with distinct properties. Sensory neurons from both mice humans express large repertoire of variants, whereas non-neuronal tissues predominantly single isoform. Notably, even within sensory ganglia, demonstrate the splicing to be cell type specific. Biophysical characterization revealed...
In mice, spared nerve injury replicates symptoms of human neuropathic pain and induces upregulation many genes in somatosensory neurons. Here we used single cell transcriptomics to probe the effects partial infraorbital transection trigeminal at cellular level. Uninjured neurons were unaffected by major branches, segregating into different classes. marked contrast, axotomy rapidly transformed damaged just two new closely-related classes where almost all original identity was lost....
In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at level of spinal cord through a top-down modulatory pathway. Although much is known about role in inhibition pain, precise directly manipulate pain-inhibitory has never been achieved. We now expose cellular circuit inhibits itch mice. Through combination molecular, tracing behavioural approaches, we found...
The mammalian odorant receptors (ORs) comprise a large family of G protein-coupled that are critical determinants both the response profile and axonal identity olfactory sensory neurons in which they expressed. Although pathway by ORs activate odor transduction is well established, mechanism direct axons into proper glomerular relationships remains unknown. We have developed gain-of-function approach using injection retroviral vectors embryonic epithelium to study ORs' contribution axon...
A remarkable feature of peripheral olfactory projections in mammals is the convergence axons from sensory neurons (OSNs) expressing same odorant receptor (OR) into glomeruli. There mounting evidence that ORs play critical roles glomerular formation. However, it remains unclear how OR exerts its function sorting homogeneity. We and others have shown previously activation G-protein/cAMP signaling cascade underlies Here, we further investigated whether establishment mature array requires...
Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer binding mode specific design parameters optimize for CNS druglike molecules, came focus on di(pyridin-2-yl)amines because their combination desirable potency good brain penetration following...
Loss of function the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits specificity cryptic splicing induced by TDP-LOF to drive expression when where disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design generate customizable events within protein-coding sequences. We demonstrate that TDP-REG reporters tightly coupled in vitro vivo....
Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling maladaptive pathways that lead following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in mouse model neuropathic pain. Furthermore, also prevents spinal cord...
The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as potentially viable treatment for Parkinson's disease. By using aminopyrazoles aniline bioisosteres, we discovered novel series inhibitors. Herein, describe our optimization effort that resulted in the identification highly potent, brain-penetrant aminopyrazole (18) addressed liabilities (e.g., poor solubility and metabolic soft spots) previously disclosed anilino-aminopyrimidine In vivo...