Document text
Principal Investigator: Matthew Reed Steinhart
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2020
Award: $37,163
Funding agency: National Institute on Deafness and Other Communication Disorders
ABSTRACT
Neurofibromatosis Type 2 (NF2) is a genetic condition in which specific types of tumors form in various
locations throughout the body. Though the majority of these tumors grow slowly, the location of certain tumors
can cause significant dysfunction. One of these tumor types grows on the vestibular branch of cranial nerve
VIII, the vestibulocochlear nerve. The cells which gives rise to this tumor type is the Schwann cell, a glial cell
type. Thus, this tumor type is termed a vestibular Schwannoma (VS), a mass of Schwann cells on the
vestibular nerve. Due to the proximity of skull base cranial elements, a VS can cause dysfunction like hearing
loss, balance issues, or facial paralysis. The current treatment options are limited to invasive surgical
procedures which can create complications. Current knowledge of the mechanisms governing the development
and growth of VS is limited due to the fact that research has been restricted to mouse and simple human cell
culture systems. This proposed study will provide vertical impact by modeling NF2 in a new system, the inner
ear organoid. Inner ear organoid induction involves step-wise differentiation in a 3D culture system using
pluripotent stem cells. Inner ear organoids develop full sensory circuits of hair cells, sensory neurons, and
myelinating Schwann cells in vitro. We will create this model by introducing a genetic manipulation in our stem
cells which mimics the genetics of NF2 patients. In Aim 1, we will analyze biochemical pathways known to be
affected in NF2 patients in this new NF2 inner ear organoid. In Aim 2, we will evaluate druggable targets in
order to assess therapeutic effectiveness to counteract the introduced NF2 mutation. This study will provide
insight into the tumorigenic processes of VS.
Terms: <3D cell culture><3D culture><Acoustic Nerve><Acoustic Neurilemmoma><Acoustic Neurilemoma><Acoustic Neurinoma><Acoustic Neuroma><Acoustic Schwannoma><Actins><Address><Adherent Culture><Affect><Afferent Neurons><Ancient Neurilemmoma><Ancient Schwannoma><Anti-Oncogenes><Antioncogenes><Axon><Basicranium><Basis cranii><Biochemical Pathway><Biology><Body Tissues><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Suppressor Genes><Cas nuclease technology><Cell Body><Cell Culture System><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Matrix><Cellular Proliferation><Central Neurofibromatosis><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Code><Coding System><Communities><Complex><Corti Cell><Cranial Base><Cranial Nerve Eight><Cranial Nerve VIII><Cytoskeletal System><Cytoskeleton><Degenerated Neurilemmoma><Degenerated Schwannoma><Development><Disease><Disorder><Drug Targeting><Drug Therapy><Dysfunction><Effectiveness><Eighth Cranial Nerve><Elements><Embryo><Embryonic><Emerogenes><Equilibrium><Facial Nerve Paralysis><Facial Palsy><Facial paralysis><Foundations><Functional disorder><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Glia><Glial Cells><Goals><Growth and Development><Growth and Development function><Hair Cells><Hearing Loss><Human><Hypoacuses><Hypoacusis><In Vitro><Internal Ear><Investigation><Investigators><Knock-out><Knockout><Knowledge><Kolliker's reticulum><Laboratories><Labyrinth><Location><Merlin><Metabolic Networks><Mice><Mice Mammals><Modeling><Modern Man><Moesin-Ezrin-Radixin-Like Protein><Monolayer culture><Murine><Mus><Mutation><NF2 Gene Product><NF2 gene><Nerve Cells><Nerve Unit><Neural Cell><Neurilemma Cell><Neurilemmal Cell><Neurilemmoma><Neurilemoma><Neurinoma><Neurocyte><Neurofibromatosis 2><Neurofibromatosis 2 Gene Product><Neurofibromatosis 2 Genes><Neurofibromatosis II><Neurofibromatosis Type 2 Protein><Neurofibromatosis Type 2s><Neurofibromin 2><Neuroglia><Neuroglial Cells><Neurons><Non-neuronal cell><Nonneuronal cell><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Operative Procedures><Operative Surgical Procedures><Organogenesis><Organoids><Pathogenesis><Pathway interactions><Patients><Peripheral><Pharmacotherapy><Phenocopy><Physiopathology><Pluripotent Stem Cells><Population><Process><Progenitor Cells><Proteins><Receptor Protein><Recessive Oncogenes><Research><Research Personnel><Researchers><Schwann Cells><Schwannoma><Schwannomerlin><Schwannomin><Schwannomin Protein><Sensory><Sensory Cell Afferent Neuron><Sensory Neurons><Spinning Sensation><Structure><Subjective Vertigo><Surgical><Surgical Interventions><Surgical Procedure><System><Tissues><Training Programs><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor Suppressor Proteins><Type 2 Neurofibromatosis><Type II Neurofibromatosis><VIIIth Cranial Nerve><Vertigo><Vestibular Nerve><Vestibular Neurilemmoma><Vestibular Root of Eighth Cranial Nerve><Vestibulocochlear Nerve><Work><acoustic neurofibromatosis><auditory nerve><balance><balance function><base><cell type><developmental><drug development><drug treatment><druggable target><dysfunctional hearing><ear hair cell><experience><experiment><experimental research><experimental study><ezrin><gene manipulation><genetic condition><genetic disorder><genetic manipulation><genetically manipulate><genetically perturb><genome mutation><hearing defect><hearing deficit><hearing difficulty><hearing disability><hearing dysfunction><hearing impairment><human model><human pluripotent stem cell><inner ear><insight><intracellular skeleton><membrane-organizing extension spike protein><model of human><moesin><mouse model><murine model><nerve cement><neuronal><nf 2 Genes><novel><oncosuppressor gene><pathophysiology><pathway><phosphoprotein p81><radixin><radixin protein><receptor><scRNA-seq><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><skull base><stem cells><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic effectiveness><therapeutic target><three dimensional cell culture><tumor><tumor suppressor><tumorigenic><vestibular Schwannoma>