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A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

Award Number: F32NS128000
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Group Awards By Issue Date FY or Funding FY:

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ABSTRACT Dystonia is neurodevelopmental disease characterized by involuntary twisting movements. Effective dystonia treatments remain elusive because the dysfunctional circuit(s) that cause and perpetuate the motor abnormalities is largely uncharacterized. One limitation to advancing our understanding of dystonia pathophysiology and developing novel therapeutic strategies is the lack of etiologically based animal models that exhibit overt dystonia-like behaviors. We overcame this limitation by engineering a mouse model that exhibits robust motor abnormalities starting in juvenile development, following a disruption of the dystonia gene, TOR1A.TorsinA, the protein that is made from the TOR1A, is important during brain development for synaptogenesis and its loss results in abnormal functional connectivity. I will use our novel mouse model to investigate how a loss of torsinA function in brain motor circuits causes dystonia. I will test a new idea: that dystonia results from sequential insults. First, genetic mutations cause a small but critical group of neurons to make aberrant anatomical connections. Then, sustained circuit dysfunction reinforces abnormal movements. These studies are possible because of multiple uniquely designed “tools" my lab has created and the advanced brain imaging methods that have been developed at UT Southwestern, where the study will be performed. This proposal will also advance our understanding of dystonia by identifying the brain circuit changes required to propagate and suppress motor dysfunction. This understanding will inform future work aimed at developing effective therapies for dystonia.


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: 2023 ( Subtotal = $74,492 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/14/2023	NON-COMPETING CONTINUATION	$74,492
														Subtotal = $74,492

Issue Date FY: 2022 ( Subtotal = $70,282 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/20/2022	NEW	$0
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/20/2022	NEW	$70,282
														Subtotal = $70,282

Grand Total All Awards = $144,774

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A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

Award Number: F32NS128000

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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