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Loss of TDP-43 disrupts the prefrontal neural activity and circuitry: relevance for TDP-43 linked ADRD

Award Number: R01NS129878
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Loss of TDP-43 disrupts the prefrontal neural activity and circuitry: relevance for TDP-43 linked ADRD - The overarching goal of this proposal is to determine the pathogenic mechanism by which loss of TAR DNA-binding protein 43 kDa (TDP-43) contributes to the earliest neural activity and network changes that precede neuron loss in disorders associated with TDP-43 pathology. Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD) are the most common forms of dementia currently without disease modifying therapy. ADRD shares many cognitive and pathological features with AD and can be clinically difficult to distinguish from AD. One of the most common non-canonical pathologic hallmarks of AD is TDP-43 proteinopathy, which occurs in ~30-57% of AD brains (AD-TDP). TDP-43 proteinopathy, first shown to be a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and in a major subtype of frontotemporal lobar degeneration (FTLD-TDP), is also found in other neurodegenerative diseases. Since cognitive decline and brain atrophy are exacerbated in AD TDP relative to AD, understanding the pathogenic role of TDP-43 in AD-TDP and FTLD-TDP that contributes to the earliest neural circuit abnormalities could facilitate identification of novel therapeutic targets and treatment strategies. Based on our preliminary studies, we hypothesize that TDP-43 plays essential roles in maintaining normal neural activity and circuitry through regulating RNA splicing of specific calcium channels. To test this hypothesis, we will take a multidisciplinary approach capitalizing on our team’s expertise in TDP-43 biology, mouse genetic and neuropathology, in vivo calcium imaging and circuit analysis in mouse models, and TDP-43 depleted cortical neurons derived from hPSC and patient-specific iPSC models. We have the following three specific aims. In Aim #1, we will perform repetitive in vivo calcium imaging to monitor calcium activity changes from the same pyramidal neurons in awake behaving mice, to determine the impact of pyramidal TDP-43 loss to the cortical network. In Aim #2, we will perform repetitive in vivo calcium imaging to determine the consequence of TDP-43 depletion specifically in inhibitory interneurons or sparsely in both excitatory and inhibitory neurons of the PFC. In Aim #3, we will use mouse models, hPSC derived cortical neurons, and patient brain tissues of AD-TDP and FTLD-TDP to determine the molecular mechanisms whereby TDP-43 loss leads to early aberrant neural activity in the PFC. We believe that our work will not only clarify early pathogenic mechanisms of TDP-43 loss but also identify novel therapeutic targets and design of effective therapeutic strategy to attenuate these devastating disorders of the elderly


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $736,565 )
2025	2025	UNIVERSITY OF WYOMING	1000 E UNIVERSITY AVE	LARAMIE	WY	82071	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/4/2025	EXTENSION WITH OR WITHOUT FUNDS	$736,565
														Subtotal = $736,565

Grand Total All Awards = $736,565

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Loss of TDP-43 disrupts the prefrontal neural activity and circuitry: relevance for TDP-43 linked ADRD

Award Number: R01NS129878

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/19/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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