A5023969163- Hearing, Cochlea, Tinnitus, Genetics
- RNA regulation and disease
- Tendon Structure and Treatment
- Developmental Biology and Gene Regulation
- Hearing Loss and Rehabilitation
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Animal Genetics and Reproduction
- Congenital heart defects research
- Glycosylation and Glycoproteins Research
- Congenital limb and hand anomalies
- Neural dynamics and brain function
- Photoreceptor and optogenetics research
- Animal Vocal Communication and Behavior
- Virus-based gene therapy research
- Connective tissue disorders research
- Sphingolipid Metabolism and Signaling
- Circadian rhythm and melatonin
- Antimicrobial Peptides and Activities
- Ear Surgery and Otitis Media
- Cancer-related molecular mechanisms research
- Metabolism and Genetic Disorders
- Microbial Inactivation Methods
- Neuroscience and Music Perception
- Mitochondrial Function and Pathology
Oregon Health & Science University
2012-2024
Oregon National Primate Research Center
2024
Oregon Dermatology & Research Center
2008
Purdue University West Lafayette
2000-2004
Medical Research Council
2000
Boston College
1992-1998
Cochlear inner hair cells (IHCs) use Ca(2+)-dependent exocytosis of glutamate to signal sound information. Otoferlin (Otof), a C(2) domain protein essential for IHC and hearing, may serve as Ca(2+) sensor in vesicle fusion IHCs that seem lack the classical neuronal sensors synaptotagmin 1 (Syt1) Syt2. Support hypothesis otoferlin function comes from biochemical experiments, but additional roles late upstream have been indicated by physiological studies. Here, we tested functional equivalence...
Studies of cell fate focus on specification, but little is known about maintenance the differentiated state. In this study, we find that mouse tendon requires continuous in vivo and identify an essential role for TGFβ signaling fate. To examine tenocyte function type II receptor (Tgfbr2) was targeted Scleraxis-expressing lineage using ScxCre deletor. Tendon development not disrupted mutant embryos, shortly after birth tenocytes lost differentiation markers reverted to a more stem/progenitor...
Congenital hearing deficits can be caused by a variety of genetic and acquired conditions. Complete reversal in the peripheral auditory system may require delivery corrective genes to cochlear progenitor cells. We tested lentivirus an array recombinant adeno-associated viral (AAV) serotypes for efficiency cellular specificity transgene expression after utero developing mouse otocyst. Stability safety with respect function were then those vectors that had most favorable transduction...
The membranous labyrinth of the inner ear establishes a precise geometrical topology so that it may subserve functions hearing and balance. How this geometry arises from simple ectodermal placode is under active investigation. invaginates to form otic cup, which deepens before pinching off vesicle. By vesicle stage many genes expressed in developing have assumed broad, asymmetrical expression domains. We been exploring possibility these domains reflect developmental compartments are...
In the vertebrate inner ear, ability to detect angular head movements lies in three semicircular canals and their sensory tissues, cristae. The molecular mechanisms underlying formation of are largely unknown. Malformations this vestibular apparatus found zebrafish mice usually involve both Although there examples mutants with only defective canals, few have normal without some prior tissue specification, suggesting that cristae, might induce non-sensory components, canals. We fate-mapped...
Vangl2 is one of the central proteins controlling establishment planar cell polarity in multiple tissues different species. Previous studies suggest that localization protein to specific intracellular microdomains crucial for its function. However, molecular mechanisms control trafficking within a are largely unknown. Here, we identify Gipc1 (GAIP C-terminus interacting 1) as new interactor Vangl2, and show myosin VI-Gipc1 complex can regulate traffic heterologous cells. Furthermore, cochlea...
The transcription factor Scleraxis (Scx) is required for tendon development; however, the function of Scx not fully understood. Although expressed by all progenitors and cells, only long tendons are disrupted in Scx−/− mutant while short appear normal ability muscle to attach skeleton affected. We recently demonstrated that formed two stages: first anchoring via a anlage, followed rapid elongation parallel with skeletal growth. Through lineage tracing, we extend these observations show...
Highlights•Superficialis myofibers form in the paw before actively translocating to arm•Muscle translocation depends on muscle contraction and tendon-muscle attachment•The intrinsic brevis extrinsic superficialis are evolutionary homologs•Superficialis formation is a later tetrapod modification brevisSummaryThe muscles that govern hand motion composed of reside within forearm hand. We find flexor digitorum (FDS) first differentiate as then relocate their final position arm. This remarkable...
Congenital diseases account for a large portion of pediatric illness. Prenatal screening and diagnosis permit early detection many genetic diseases. Fetal therapeutic strategies to manage disease processes in utero represent powerful new approach clinical care. A safe effective fetal pharmacotherapy designed modulate gene expression ideally would avoid direct mechanical engagement the fetus present an external reservoir drug. The amniotic cavity surrounding could serve as ideal drug...
Zika virus infection during pregnancy is associated with miscarriage and a broad spectrum of fetal neonatal developmental abnormalities collectively known as congenital syndrome (CZS). Symptomology CZS includes malformations the brain skull, neurodevelopmental delay, seizures, joint contractures, hearing loss visual impairment. Previous studies in pregnant rhesus macaques (Macaca mulatta) have described injury to developing fetus loss, but outcomes following exposure yet be characterized...
Disabling hearing loss impacts ∼466 million individuals worldwide with 34 children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction a mutation the fetal inner ear prior maturation sensory epithelium will optimally restore function. previously demonstrated transuterine...
Abstract Mutations in the MYO7A gene lead to Usher syndrome type 1B (USH1B), a disease characterized by congenital deafness, vision loss, and balance impairment. To create nonhuman primate (NHP) USH1B model, CRISPR/Cas9 was used disrupt rhesus macaque zygotes. The targeting efficiency of Cas9 mRNA hybridized crRNA-tracrRNA (hyb-gRNA) compared nuclease (Nuc) protein synthetic single guide (sg)RNAs. Nuc/sgRNA injection led higher editing efficiencies relative mRNA/hyb-gRNAs. were assessed...
Therapeutic strategies to restore hearing and balance in mouse models of inner ear disease aim rescue sensory function by gene replacement, augmentation, knock down or out. Modalities achieve therapeutic effects have utilized virus-mediated transfer wild type genes small interfering ribonucleic acids; systemic focal administration antisense oligonucleotides designer molecules; lipid-mediated Cas 9 ribonucleoprotein complexes. This work has established that drug the structurally functionally...
The mammalian inner ear subserves the special senses of hearing and balance. auditory vestibular sensory epithelia consist mechanically sensitive hair cells associated supporting cells. Hearing loss balance dysfunction are most frequently caused by compromise and/or their innervating neurons. development gene- cell-based therapeutics will benefit from a thorough understanding molecular basis patterning cell fate specification in ear. This includes analyses lineages dispersals across...
Abstract: The El (epileptic) mouse is considered a model for complex partial seizures in humans. Seizures mice begin around 7–8 weeks of age and persist throughout life. To determine if astrocytic gliosis was present adult seizing mice, the distribution glial fibrillary acidic protein (GFAP) studied hippocampus using an antibody to GFAP. mean number GFAP‐positive cells per square millimeter approximately 15‐ 40‐fold higher than nonseizing control C57BL/ 6J (B6) or young mice. Relative GFAP...
The mammalian inner ear has 6 distinct sensory epithelia: 3 cristae in the ampullae of semicircular canals; maculae utricle and saccule; organ Corti coiled cochlea. contain vestibular hair cells that transduce mechanical stimuli to subserve special sense balance, while auditory are primary transducers for hearing 1. Cell fate specification these epithelia morphogenesis canals cochlea take place during second week gestation mouse largely completed before birth 2,3. Developmental studies...
Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection female germline is thought to be responsible elimination most harmful during oogenesis. Here we show that deleterious abundant ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not their live offspring. This implies purifying acts maternal per se,...