Friday, November 22, 2024 11/22/2024

Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem Cells

Award Number: R01NS100529
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder that primarily affects neurons in the striatum and cortex. Studies have identified striatal developmental impairments in HD and transcriptional pathways that are amenable to disease-modifying interventions. Our central hypothesis is that HD MSNs manifest developmental alterations that cause their dysfunction, dedifferentiation and potentially dysregulation with inappropriate neuronal markers for MSNs. We further hypothesize that these HD phenotypes can be corrected by modulating MSN developmental transcription factors or via drugs that correct transcriptional dysregulation. Specifically, the failure of HD MSNs to differentiate properly makes them more susceptible to neurodegeneration. Therefore, we can use our newly discovered MSN transcription factors to rescue this HD phenotype. The early developmental alterations in MSNs set the stage for developing HD symptoms later in life. In support of this hypothesis: 1) the maturation or maintenance of medium spiny neurons (MSNs) is dysregulated in human isogenic HD-iPSCs with corrected alleles; 2) that the developmental trajectory is distinct and alters the DLX gene family, key MSN developmental transcription factors, as determined by bulk and scRNAseq; 3) using bioinformatics, drugs can be identified that can be repurposed to rescue this altered developmental trajectory; 4) the key developmental MSN transcription factor, Bcl11b (also known as Ctip2), is also a key maintenance factor in the mature MSNs, as conditional and specific deletion in postnatal mouse MSNs converts their transcriptome to one that mimics human and mouse HD gene expression and 5) identification of novel TFs required for striatal compartmentation and striosome maturation may be potential HD therapeutic targets. Therefore, the specific aims are: Specific Aim 1 will characterize the cellular, developmental and functional deficits in human isogenic HD-MSNs derived from induced pluripotent stem cells, and evaluate if predicted key TFs or drugs rescue HD phenotypes; Specific Aim 2 will characterize the cellular, developmental and functional deficits in isogenic human HD-organoids (structural organization and diversity of cells) and evaluate if predicted key TFs or drugs rescue HD phenotypes. Specific Aim 3 will determine if overexpression of MSN TFs corrects abnormalities in the Q175 mouse model with focus on the striosomal compartment. These studies will advance our understanding of how to model HD in striatal MSNs/organoids and identify novel mechanistic pathways and therapeutic targets for HD.


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: 2024 ( Subtotal = $809,186 )
2024	2024	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	5/3/2024	COMPETING CONTINUATION	$809,186
2024	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $809,186

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $614,226 )
2020	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/27/2020	NON-COMPETING CONTINUATION	$614,226
														Subtotal = $614,226

Issue Date FY: 2019 ( Subtotal = $616,060 )
2019	2019	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	9/6/2019	NON-COMPETING CONTINUATION	$616,060
2019	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/6/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $616,060

Issue Date FY: 2018 ( Subtotal = $621,319 )
2018	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/21/2018	NON-COMPETING CONTINUATION	$621,319
														Subtotal = $621,319

Issue Date FY: 2017 ( Subtotal = $649,866 )
2017	2017	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/3/2017	NON-COMPETING CONTINUATION	$649,866
														Subtotal = $649,866

Issue Date FY: 2016 ( Subtotal = $699,638 )
2016	2016	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BOULEVARD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/26/2016	NEW	$699,638
														Subtotal = $699,638

Grand Total All Awards = $4,010,295

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Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem Cells

Award Number: R01NS100529

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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