Tuesday, July 1, 2025 7/1/2025

La Spada Outstanding Investigator Award

Award Number: R35NS122140
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: 05/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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La Spada Outstanding Investigator Award - Abstract I have been studying neurodegenerative disease for more than 30 years. While a graduate student, I identified the cause of X-linked spinal and bulbar muscular atrophy (SBMA) as the expansion of a CAG repeat in the androgen receptor (AR) gene. As the first disorder shown to be caused by a CAG – polyglutamine (polyQ) repeat tract, this discovery led to the emergence of a new field. My research program began with emphasis on 2 polyQ disorders: SBMA and spinocerebellar ataxia type 7 (SCA7). My early work established transcription dysregulation as a key factor in polyQ disease pathogenesis. I initiated research on Huntington’s disease (HD), and linked mitochondrial dysfunction and metabolic deficits in HD to transcription dysregulation of PGC-1a, a transcription co-activator. In 2016, I documented an interaction between PPARd and huntingtin (htt) protein in striatal-like neurons and in the cerebral cortex of HD mice, and I demonstrated that PPARd repression contributes to HD neurotoxicity. These findings led me to repurpose a selective and potent PPARd agonist, KD3010, as capable of rescuing htt neurotoxicity in HD transgenic mice and in medium spiny neurons from HD patient stem cells. Concomitant with my HD research, I uncovered a central role for skeletal muscle in SBMA by demonstrating that excision of mutant AR transgene from skeletal muscle in BAC conditional transgenic mice prevented the development of neuromuscular SBMA phenotypes, establishing the importance of skeletal muscle – motor neuron (MN) communication at the neuromuscular junction (NMJ) for SBMA lower MN disease. I have thus continuously maintained NINDS R01 funding to support my SBMA research since 2000, and have held NINDS R01 funding to support my HD research since 2010. During this time frame, my research has increasingly focused on identification of targets and pathways for development of therapies. As a R35 recipient, I will continue my research on the cellular and molecular basis of polyQ neurodegeneration, embracing opportunities to extend our findings to more common neurodegenerative diseases, including AD, PD, and ALS. One major focus will be to define the basis of SBMA muscle-driven MN disease through skeletal muscle and NMJ transcriptome analysis of SBMA model mice and stem cell modeling to recapitulate non-cell autonomous SBMA MN degeneration. I also intend to pursue studies of HD and PPARd by determining the normal function of PPARd in CNS and defining how PPARd activation achieves neuroprotection. I will follow up on exciting findings linking PPARd neuroprotection to regulation of neuronal activity-dependent gene expression, and will test if blunting of rapid primary response gene expression can ameliorate HD phenotypes. As PPARd is highly expressed in microglia and represses neuroinflammation, I will study PPARd function in microglia and test if PPARd dysregulation plays a role in neurodegenerative disease. R35 funding would provide me with the flexibility to pursue novel, ambitious studies of polyQ disease, expand my research program to encompass emerging areas of pathogenesis, and maintain a lasting commitment to translational research and therapy development for neurodegeneration.


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 = $1,162,302 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/9/2025	NON-COMPETING CONTINUATION	$1,162,302
														Subtotal = $1,162,302

Issue Date FY: 2024 ( Subtotal = $1,127,433 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/11/2024	NON-COMPETING CONTINUATION	$1,127,433
														Subtotal = $1,127,433

Issue Date FY: 2023 ( Subtotal = $1,162,302 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/5/2023	NON-COMPETING CONTINUATION	$1,162,302
														Subtotal = $1,162,302

Issue Date FY: 2022 ( Subtotal = $1,554,713 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/6/2022	NON-COMPETING CONTINUATION	$1,162,302
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/28/2022	SUPPLEMENT FOR EXPANSION	$392,411
														Subtotal = $1,554,713

Issue Date FY: 2021 ( Subtotal = $995,408 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/24/2021	NEW	$0
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/4/2021	NEW	$995,408
														Subtotal = $995,408

Grand Total All Awards = $6,002,158

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La Spada Outstanding Investigator Award

Award Number: R35NS122140

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: 05/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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