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La Spada Outstanding Investigator Award

拉斯帕达杰出研究者奖

基本信息

批准号：
10618880
负责人：
ALBERT R LA SPADA
金额：
$ 116.23万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2029-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618880
关键词：
AR gene Aging Agonist Androgen Receptor Area Award Bacterial Artificial Chromosomes CAG repeat Cerebral cortex Communication Corpus striatum structure Development Disease Excision Functional disorder Funding Gene Expression Genetic Transcription Grant Homeostasis Huntington Disease Huntington gene Inherited Investigation Link Lower Motor Neuron Disease Metabolic Microglia Molecular Motor Neuron Disease Motor Neurons Mus Muscular Atrophy National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neurons PPAR delta Paper Pathogenesis Pathway interactions Patients Phenotype Process Publishing Regulation Repression Research Research Personnel Role Series Skeletal Muscle Testing Time Transcription Coactivator Transgenes Transgenic Mice Translational Research Type 7 Spinocerebellar Ataxia Work career disease phenotype flexibility follow-up functional decline graduate student mitochondrial dysfunction motor neuron degeneration mouse model mutant nervous system disorder neuroinflammation neuromuscular neuroprotection neurotoxicity novel novel therapeutics polyglutamine prevent programs research and development response skeletal muscle wasting spinal and bulbar muscular atrophy stem cell model stem cells therapy development transcriptome

项目摘要

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.

摘要

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.

DOI：
10.1186/s40478-023-01665-z
发表时间：
2023-10-17
期刊：
Acta neuropathologica communications
影响因子：
7.1
作者：
通讯作者：

SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease.

DOI：
10.1002/mgg3.1745
发表时间：
2021-12
期刊：
Molecular genetics & genomic medicine
影响因子：
2
作者：
Bennett CL;La Spada AR
通讯作者：
La Spada AR

De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.

DOI：
10.1186/s40478-021-01277-5
发表时间：
2021-12-18
期刊：
Acta neuropathologica communications
影响因子：
7.1
作者：
Hadjinicolaou A;Ngo KJ;Conway DY;Provias JP;Baker SK;Brady LI;Bennett CL;La Spada AR;Fogel BL;Yoon G
通讯作者：
Yoon G

X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease.