Interneurons as Early Drivers of Huntington´s Disease Progression

中间神经元是亨廷顿病进展的早期驱动因素

基本信息

批准号：
10672973
负责人：
Mark F Mehler
金额：
$ 69.9万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672973
关键词：
Ablation Address Adult Affect Age Allografting Animal Model Autopsy Behavioral Brain Brain region Cell Transplantation Cells Cerebral cortex Characteristics Clinical Code Complement Corpus striatum structure Coupling DNA Damage Data Development Developmental Process Disease Disease Progression Disease model Effectiveness of Interventions Embryo Event Exons Exposure to Foundations Functional disorder Genes Genetic Genetic Diseases Genetic Polymorphism Goals Human Huntington Disease Huntington gene Impairment Interneurons Intervention Knowledge Laboratories Laboratory Study Late-Onset Disorder Lead Length Life Ligands Link Literature Mediating Mission Motor Mus Neonatal Neurodegenerative Disorders New York Nucleotides Onset of illness Outcome Output Pathogenesis Pathogenicity Pathologic Pathology Phase Predictive Value Prevention Public Health Reporting Research Role Specimen Stress Supplementation System Testing Therapeutic Therapeutic Intervention Time Transplantation Trinucleotide Repeat Expansion Trinucleotide Repeats United States National Institutes of Health Universities age related cell type critical developmental period critical period developmental disease developmental plasticity effectiveness evaluation excitotoxicity experimental study gamma-Aminobutyric Acid genetic approach innovation insight intervention effect motor deficit motor disorder motor impairment mouse model mutant neural network neurogenesis neuroimaging neuropathology novel postnatal postnatal period preclinical study prevent pup receptor regenerative approach response restoration stem cells targeted treatment therapeutically effective trait white matter

项目摘要

Huntington’s disease (HD) is an insidious neurodegenerative disorder caused by trinucleotide repeat expansion in exon 1 of the gene that codes for Huntingtin (mHtt). The pathogenic mechanisms underlying HD remain poorly understood. Studies of HD models have documented numerous developmental impairments during ‘pre- manifest’ HD. Using conditional HD models, the Mehler laboratory team has previously shown that such developmental processes mediate disease pathogenesis. Now, this team provides evidence demonstrating that interneuron neurogenesis is prominently disrupted in mouse models of HD, leading to deficits in the complement of these interneurons within the developing cerebral cortex. Such deficits are of great importance, as studies have shown these lead to permanent changes in cortico-striatal connectivity laying the foundation for cortical hyperexcitability, impaired excitation-inhibition coupling, and striatal excitotoxic stress later in life. Although cortical interneuron deficits have previously been reported in HD cases, their role in HD pathogenesis has never been further interrogated. This application tests the central hypothesis that HD is caused by impairments in the developmental elaboration of selective cortical interneuron subtypes; therefore, prevention of the adverse developmental effects of these interneuron deficits will ameliorate or even prevent disease occurrence. This hypothesis is further supported by preliminary data showing that genetic rescue of developing interneurons precludes the onset of characteristic features of HD in BACHD mice: motor coordination deficits, hypomyelination of subcortical white matter tracts and striatal degeneration. Specific Aim 1 (SA1) initially defines whether interneuron progenitor cell supplementation via heterochronic grafts into mutant neonatal pups favorably modifies the occurrence of motor deficits and striatal degeneration, two distinctive traits of HD. This aim also examines whether the role of interneurons in disease progression takes place at the expense of quantitative deficits or through additional factors associated with expression of mutant huntingtin in these cells. SA2 interrogates the interneuron-dependent pathogenic mechanisms mediating HD, focusing on putative modulatory effects of GABA, Reelin and complementary ligand release. Finally, SA3 employs a large array of HD postmortem specimens from two major brain banks to define the role in disease progression of cortical interneuron deficits. This aim also interrogates whether known HD genetic modifiers, including trinucleotide expansion length and/or polymorphisms of DNA damage response genes modulate the extent of interneuron alterations, as well as whether these cells mediate the predictive effects of these genetic modifiers on age at disease onset/progression. Overall, confirmation of the central hypothesis would have substantial implications for the field, as it will provide strong evidence regarding the intersectional roles of interneurons in HD pathogenesis and also define a novel early-stage therapeutic window for preventing HD onset and progression for a neurodegenerative disorder currently lacking substantive and effective therapeutic interventions.

亨廷顿氏病（HD）是由三核苷酸重复扩张引起的阴险神经退行性疾病在编码亨廷顿（MHTT）的基因的外显子中。高清基础的致病机制保持较差理解。高清模型的研究记录了在“预审进期间的许多发育障碍” 清单的高清。使用有条件的高清模型，Mehler实验室团队以前已经表明发育过程培养基发病机理。现在，该团队提供了证据，表明在HD的小鼠模型中，神经元神经发生显着破坏，导致在完成中定义在发育中的大脑皮层中的这些中间神经元中。由于研究，这种缺陷非常重要已经表明了这些导致皮质 - 纹状体连通性永久变化，为皮质奠定了基础过度兴奋，兴奋性抑制偶联受损以及纹状体兴奋性应激以后的生活。虽然先前在HD病例中报道了皮质间神经元缺陷，它们在HD发病机理中的作用从来没有被进一步审问。该申请检验了中心假设，即HD是由损害引起的选择性皮质间神经元亚型的发展阐述；因此，预防逆境这些中间缺陷的发育效果将改善甚至预防疾病。这初步数据进一步支持了假设排除BACHD小鼠中HD特征特征的发作：运动配位定义，低切术皮质下白质和纹状体变性。特定目标1（SA1）最初定义是否定义通过异缘移植物补充神经元的祖细胞中的祖细胞细胞成神经新生儿幼崽修改运动缺陷和纹状体变性的发生，这是两个独特的高清特征。这个目标也是如此检查中间神经元在疾病进展中的作用是否以定量为代价缺乏或通过与这些细胞中突变亨廷汀表达相关的其他因素。 SA2 询问介导HD的依赖性依赖性的致病机制，重点是推定调节 GABA，reelin和完整配体释放的效果。最后，SA3员工大量的高清验尸从两个主要的脑库的标本来定义皮质进展中的作用中间神经元缺陷。该目标还询问已知的HD遗传修饰剂，包括三核苷酸 DNA损伤反应基因的膨胀长度和/或多态性调节中间神经元的程度改变，以及这些细胞是否介导了这些遗传修饰符对年龄的预测效应疾病发作/进展。总体而言，确认中心假设将具有实质性的影响对于该领域，它将提供有关高清中间神经元的有力证据发病机理，还定义了一种新的早期治疗窗口，以防止HD发作和进展对于目前缺乏实质性有效治疗干预措施的神经退行性疾病。