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Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum

功能失调的 BDNF 对帕金森纹状体多巴胺末端重塑的影响

基本信息

批准号：
10317097
负责人：
KATHY Steece STEECE-COLLIER
金额：
$ 34.74万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317097
关键词：
Age Aging Alleles Antiparkinson Agents BDNF gene Behavioral Biological Models Brain Brain-Derived Neurotrophic Factor Cells Clinical Clinical Trials Clinical Trials Design Consensus Corpus striatum structure Data Dendritic Spines Disease Progression Dopamine Dose Elderly Embryo Engraftment Future Genes Genetic Polymorphism Graft Survival Heterogeneity Human Impairment Individual Inferior Knock-in Length Levodopa Medical Messenger RNA Microdialysis Modeling Motor Movement Disorder Society Unified Parkinson&apos s Disease Rating Scale Nature Neurites Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Oral Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Persons Play Population Preclinical Testing Prevalence Rat-1 Rattus Reporting Research Risk Factors Role Severity of illness Signal Transduction Single Nucleotide Polymorphism Stress Supplementation Synapses Testing Therapeutic Transplantation Treatment Efficacy Uncertainty Up-Regulation Variant aged aging brain brain dysfunction cohort density dopamine graft dopaminergic neuron experience genetic risk factor genetic variant in vivo interest neural graft normal aging novel parkinsonian rodent pre-clinical regenerative regenerative approach release factor response restoration risk variant side effect standard of care synaptogenesis tool transcription factor treatment response

项目摘要

While there are a number of therapeutic options for individuals with Parkinson's disease (PD) these therapies do not work uniformly well in all patients. Indeed, a recent retrospective analysis of the ELLDOPA study reported that early-stage PD subjects receiving equivalent levodopa doses experienced a magnitude of response ranging from a 100% improvement to a 242% worsening as assessed with the United Parkinson's Disease Rating Scale part III (UPDRS-III, motor subscore). This example underscores the incredible heterogeneity in clinical response to standard-of-care anti-parkinsonian therapy, even when disease severity is taken into account. Similar findings have been reported over the past several decades for the experimental regenerative approach of neural grafting. While some PD patients have shown marked and lasting benefit following engraftment of primary dopamine (DA) neurons, many have also shown no or limited benefit. Recent preclinical data in aged parkinsonian rats together with that from two milestone clinical reports provide compelling and sobering data demonstrating that even when robust survival of grafted DA neurons and extensive neurite outgrowth is achieved, obstacle(s) remain that interfere with functional circuit restoration within the aged, parkinsonian brain. As clinical grafting trials are reemerging, it remains uncertain what specific risk factors negatively impact clinical responsiveness to DA terminal remodeling. In attempt to deconstructing the complexity of PD and response to therapy, we recently identified one candidate genetic variant, with prevalence of up to 40% in the human population, which may prove useful in this regard; specifically, a functional single nucleotide polymorphism (SNP) rs6265 in the Bdnf gene for brain-derived neurotrophic factor (BDNF) that results in dysfunctional BDNF release. We have recently observed diminished therapeutic efficacy of oral levodopa in two distinct cohorts of PD patients with this SNP risk allele. In the current application we propose to test the hypothesis that this risk allele also underlies the variability in clinical response to DA neuron grafting in PD patients. Specifically, we hypothesize that BDNF is an unrecognized contributor to the discordant finding of abundant survival of grafted DA neurons and lack of behavioral efficacy reported in a subpopulation of PD patients and in association with normal aging in parkinsonian rats. In this application we propose three Specific Aims to test the overarching hypothesis that impaired BDNF signaling, either through this common SNP and/or advanced age, is a key factor in limiting functional DA terminal remodeling. Toward this end, we have generated a knock-in rat model of the human rs6265 BDNF variant and propose to use this novel tool to characterize its effects and interaction with aging and DA-depletion on the function and synaptic integration of new DA terminals in the parkinsonian striatum using neural grafting as a model system.

虽然有许多治疗选择与个体帕金森病（PD）这些疗法