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Chemogenetic Inactivation of the Primate Internal Globus Pallidus as a treatment for Parkinsonism

灵长类内部苍白球的化学遗传学灭活治疗帕金森病

基本信息

批准号：
10577404
负责人：
Adriana Galvan
金额：
$ 45.5万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-27 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577404
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acetylcholine Acute Adverse effects Affinity Animal Model Animals Anions Antiparkinson Agents Autopsy Basal Ganglia Behavioral Binding Brain Brain region Cell Nucleus Chronic Clinical Corpus striatum structure Data Devices Dopamine Dose Electrons Electrophysiology (science)FDA approved Gliosis Globus Pallidus Glycine Receptors Goals Gold Histologic Infection Ion Channel Gating Ions Lead Levodopa Ligand Binding Domain Ligands Light Long-Term Effects Longevity MPTP Poisoning Macaca mulatta Mediating Methods Microscopic Modeling Monkeys Motor Motor Neurons Movement Mutate National Institute of Neurological Disorders and Stroke Neurons Operative Surgical Procedures Output Parkinson Disease Parkinsonian Disorders Pathologic Patients Pattern Penetration Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Physiological Primates Specific qualifier value Specificity Surface System Techniques Testing Therapeutic Translations Viral Viral Vector Work alpha-bungarotoxin receptor awake base clinical practice effective therapy expectation experimental study extracellular histological studies human disease minimally invasive motor impairment motor symptom neuroinflammation neuronal patterning neurotoxic nigrostriatal dopaminergic pathway nonhuman primate novel novel strategies parkinsonian non-human primate receptor receptor expression response side effect smoking cessation symptom treatment treatment strategy varenicline

项目摘要

PROJECT SUMMARY Parkinson’s disease (PD) leads to disabling motor impairments, resulting from the degeneration of the dopaminergic nigrostriatal pathway and a loss of dopamine in the striatum. These pathological changes alter the neuronal activity throughout the basal ganglia. One of the salient changes is that the activity in the motor portion of the internal pallidal segment (GPi) is increased and abnormally patterned. The currently available medication or neurosurgical treatments for the symptoms of PD are encumbered by unwanted side effects that frequently limit their use in patients. Many of the adverse effects of the current therapies undoubtedly result from their lack of cellular or brain circuit specificity. Minimally invasive methods to reversibly modulate neurons in a selective manner in the motor territory of the basal ganglia could provide an alternative approach to alleviate parkinsonism without side effects. We hypothesize that chemogenetic methods that target genetically specified neurons may be a safer, and at least equally effective alternative. Chemogenetic techniques involve the expression (through viral vectors) of artificial receptors in specific neurons. These receptors can then be activated by systemically administered compounds that are otherwise inert. In the planned experiments, we will use a novel chemogenetic approach, based on the expression of receptor-modulated ligand-gated ion channels, to reduce GPi activity in rhesus monkeys that have been rendered stably parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). The phenotypic and physiologic similarities between MPTP-induced parkinsonism and PD make the MPTP-treated monkey an excellent model for this purpose. We have strong preliminary results indicating that the chemogenetic receptors we plan to use (“Pharmacologically selective actuator molecules” (PSAMs)) can be successfully expressed in GPi neurons of monkeys using viral vectors, and that systemic administration of PSAM-activating compounds ameliorate GPi activity, with accompanying changes in movement. We now plan to evaluate the antiparkinsonian effects of PSAM-mediated inactivation of GPi in MPTP- treated monkeys (aim 1). In the course of these experiments, we will study the effects of acute or chronic administration of two PSAM-activating compounds (low doses of varenicline, a clinically approved smoking cessation drug, or a newly generated “pharmacologically selective effector molecule” (PSEM)). The responses to these drugs will be compared to those of the gold-standard antiparkinsonian medication, levodopa. Under aim 2, we will examine the pattern and longevity of the PSAM expression in the GPi and will histologically verify that chronic use of these chemogenetic therapeutic methods do not have identifiable neurotoxic effects. The proposed studies will help us to develop the PSAM approach into a treatment for parkinsonism, that could offer notable advantages over the currently available therapies.

项目总结