Interrogating maladaptive serotonin raphe-striatal plasticity in l-dopa-induced dyskinesia

Active Project Grant Awarded Last action

Award ID
R01NS122226
Recipient
Awarding agency
Obligated
$10,513,305

Award facts

Completion date 98% complete
Place of performance
Binghamton, NY 13902, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
L-dopa remains the gold-standard treatment for parkinson's disease (PD). Unfortunately, within a decade of commencing l-dopa, nearly 90% of PD patients develop intractable abnormal involuntary movements known as l- dopa-induced dyskinesias (lid), severely impacting quality of life. Research implicates serotonin (5-HT) neurons as a source of lid as they can take up l-dopa, convert IT to dopamine (DA), and release DA as an unregulated "false neurotransmitter" leading to a dyskinesogenic phenotype. Although treatments aimed at alleviating lid have emerged, only a minority of patients benefit due to their cost, side effects and/or invasiveness. Moreover, we have yet to find a way to prevent lid development, in part due to major gaps in knowledge on how l-dopa treatment instigates maladaptive 5-HT reorganization and aberrant striatal output. Our research team has recently collected preliminary data using novel approaches that provide exciting new insights into the mechanisms of 5-HT neuroplasticity that will enlighten both basic and clinical science. These convergent findings led US to postulate our central hypothesis that maladaptive 5-HT-raphe-striatal neurocircuit plasticity precipitates and maintains lid. The overarching goal for our multi-investigator team is to identify the mechanisms underlying the development of structural and functional maladaptation within the raphe-striatal circuit driving lid, which in turn could lead to novel, optimized targets for intervention. We will fill this knowledge GAP through the pursuit of 3 independent, but inter-related specific aims. Our 3 specific aims will: 1) define the extent to which DA denervation and/or l-dopa treatment results in anatomical and functional reorganization of the 5-HT raphe- striatal pathway in PD and experimental parkinsonism, 2) use projection-specific chemogenetic modulations to determine the impact of the 5-HT raphe-striatal activity on l-dopa-induced anti-parkinsonian efficacy and dyskinesia, and 3) establish how regulating DA release from 5-HT raphe-striatal neurons prevents the development of lid and associated maladaptive neuronal changes. The proposed cross-species investigation will establish neuroplasticity within the 5-HT raphe-striatal circuit as a foremost factor in the development and expression of lid and in so doing, identify optimal treatment strategies to improve the quality of life for millions of current and prospective PD patients.

Transactions

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Subawards

Subrecipient Amount Awarded
Dignity Health L-DOPA remains the gold-standard treatment for Parkinson’s disease (PD). Unfortunately, within a decade of commencing L-DOPA, nearly 90% of PD patients… $839,521
Banner Health Banner Health will provide Dr. Bishop’s team with autopsied raphe, caudate and putamen specimens of neuropathologically characterized human subjects from… $43,527
Mayo Clinic Arizona Dr. Adler is the Co-Investigator. His role is to perform movement disorder examinations on subjects enrolled as well as oversee the clinical assessments of… $81,578
University Of Illinois Dr. Kuei Tseng, MD & PhD, Professor of Anatomy & Cell Biology, University of Illinois Chicago – College of Medicine, will be responsible for all… $599,972
University Of Illinois $585,852
Banner Health Banner Health will provide Dr. Bishop’s team with autopsied raphe, caudate and putamen specimens of neuropathologically characterized human subjects from… $32,149
Cold Spring Harbor Laboratory The Zador lab developed the MAPseq and BARseq techniques. Our role will be to participate in the experimental design, exploiting our understanding of the… $140,048

Quick answers

Who received award R01NS122226?

R01NS122226 was awarded to The Research Foundation For The State University Of New York by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on December 1, 2021.

How much is award R01NS122226 worth?

$10,513,305 has been obligated on R01NS122226.

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