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Principal Investigator: Fen-Biao Gao
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $634,466
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Frontotemporal dementia (FTD) is a progressive neurodegenerative disease associated with focal atrophy of
the prefrontal and/or temporal lobes. FTD is the second most common form of dementia among people under
the age of 65. Many FTD-causing genes have been identified during the last decade, including CHMP2B,
GRN, C9ORF72, and TBK1. Some of these genes are also implicated in the motor neuron disease
amyotrophic lateral sclerosis (ALS), paving the way for in-depth mechanistic investigation of pathogenic
processes in both disorders. In order to reveal common pathogenic mechanisms in different forms of FTD, it is
critically important to investigate both common and rare genetic mutations. To this end, in this application, we
will focus on the effects of FTD-causing mutations in CHMP2B and TBK1 on the functions of the endosomal-
lysosomal and autophagy pathways, two closely linked cellular pathways for degradation of transmembrane
and intracellular cargos. We will take advantage of strengths of different experimental systems including fruitfly
Drosophila, mouse models of FTD and cortical neurons differentiated from CRISPR-engineered induced
pluripotent stem cells (iPSCs). This multidisciplinary approach will greatly enhance our understanding of
pathogenic mechanisms of FTD and reveal novel targets for therapeutic intervention.
Terms: <Address><Affect><Age><Amentia><American><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Anterior><Atrophic><Atrophy><Autophagocytosis><C9ORF72><CRISPR><CRISPR/Cas system><Cell Line><CellLine><Chromosome 3><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><DNA Alteration><DNA Sequence Alteration><DNA mutation><Defect><Degenerative Neurologic Disorders><Degradation Pathway><Degradative Pathway><Dementia><Diagnosis><Disease><Disorder><Disturbance in cognition><Drosophila><Drosophila genus><Endosomes><Engineering><Exhibits><FLJ11330><FTD/ALS><FTLD/ALS><Family><Frontal Temporal Dementia><Frontotemporal Dementia><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Gehrig's Disease><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Human><Impaired cognition><Induced pluripotent stem cell derived neurons><Investigation><Language><Link><Lou Gehrig Disease><Membrane><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Motor Neuron Disease><Murine><Mus><Muscle Atrophy><Muscular Atrophy><Mutation><Myosin B><Myosin IIB><NF-Kb-Activating Kinase Gene><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neuronal Differentiation><Neurons><Non-Muscle Myosin Type IIB><Nonmuscle Myosin Type IIB><Palsy><Paralysed><Pathogenicity><Pathologic><Pathway interactions><Patients><Personality><Persons><Plegia><Process><Production><Proteins><Receptosomes><Recycling><Research><Sequence Alteration><Series><Social Behavior><Strains Cell Lines><System><T2K><TBK1><TBK1 gene><Temporal Lobe><Testing><Therapeutic Intervention><Toxic effect><Toxicities><Work><ages><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><autophagy><behavior phenotype><behavioral phenotyping><chromosome 9 open reading frame 72><clinical phenotype><cognitive dysfunction><cognitive loss><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative disorder of motor neurons><degenerative neurological diseases><discover genes><experiment><experimental research><experimental study><experiments><front temporal dementia><frontal lobe dementia><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia><frontotemporal lobar dementia amyotrophic lateral sclerosis><frontotemporal lobe degeneration associated with dementia><fruit fly><gene discovery><genome mutation><genomic alteration><iPS><iPS neurons><iPSC><iPSC derived-neurons><iPSCs><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell neurons><inducible pluripotent stem cell><insight><interdisciplinary approach><intervention therapy><membrane structure><mouse model><multidisciplinary approach><murine model><muscle breakdown><muscle degradation><muscle deterioration><muscle loss><muscle wasting><mutant><neural circuit><neural circuitry><neural degeneration><neurocircuitry><neurodegeneration><neurodegenerative><neurodegenerative illness><neurodegenerative phenotype><neurological degeneration><neuronal><neuronal degeneration><neurons derived from induced pluripotent stem cells><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><paralysis><paralytic><pathway><prefrontal lobe><progenitor cell model><progenitor model><programs><sociobehavior><sociobehavioral><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><synaptic circuit><synaptic circuitry><syntaxin 13><temporal cortex><therapeutic agent development><therapeutic development><therapeutic target>