Huntington's disease: a novel developmental oligodendrogliopathy

亨廷顿病：一种新型的发育性少突胶质细胞病

基本信息

批准号：
9233213
负责人：
Mark F Mehler
金额：
$ 36.53万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233213
关键词：
Ablation Address Adult Alzheimer&apos s Disease Architecture Biological Markers Cells Ceroid Characteristics Chronic Cognitive Complement Corpus striatum structure Data Defect Demyelinations Dentatorubral-Pallidoluysian Atrophies Development Disease Disease Outcome Disease Progression Dorsal Exhibits Functional disorder Ganglia Genes Genetic Goals Gray unit of radiation dose Human Huntington Disease Huntington gene Impaired cognition Impairment Intervention Knock-in Knock-in Mouse Lateral Lead Life Medial Mediating Modeling Molecular Molecular Genetics Motor Multiple System Atrophy Myelin Nature Nerve Degeneration Neurodegenerative Disorders Neurons Oligodendroglia Onset of illness Outcome Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Phase Phenotype Play Prosencephalon Replacement Therapy Reporter Research Role Secondary to Specimen Supporting Cell Testing Therapeutic Therapeutic Intervention Therapeutic Studies Transplantation White Matter Disease Work base disability genetic manipulation innovation insight motor deficit mouse model mutant myelination nervous system disorder neurodevelopment neuron loss neuropsychiatry new therapeutic target novel oligodendrocyte lineage oligodendrocyte precursor postnatal prevent programs public health relevance relating to nervous system selective expression stem targeted treatment time use white matter

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease: a novel developmental oligodendrogliopathy Huntington's disease (HD) is a relentlessly progressive neurodegenerative disorder that typically presents with progressive cognitive/motor deficits. Although HD exhibits a unitary genetic basis (mutant huntingtin [mHtt]), our understanding of HD pathogenesis remains poorly defined. The hallmark of HD is degeneration of striatal medium spiny neurons (MSNs). Therefore, study of HD has focused predominantly on cell autonomous mechanisms mediating MSN death. However, there is increasing recognition that HD pathology also encompasses dysfunction of oligodendrocytes (OLs), myelin and white matter tracts (WMTs). These defects occur during prodromal phases of HD, suggesting that non-cell autonomous mechanisms mediated by OLs may play important roles in HD pathogenesis. Here, we test the hypothesis that postnatal WMT abnormalities are: (1) secondary to defects in the second wave of developmental forebrain oligodendrogliogenesis leading to ectopic persistence of non-myelinating OLs from the first wave, and (2) necessary for region-specific profiles of forebrain vulnerability to neurodegeneration. This developmental hypothesis is based on our experimental data showing: (1) impairments in multiple NSC-mediated MSN developmental parameters in a HD knock-in mouse model, (2) early and stable OL impairments in HD mouse models/human pathological specimens, (3) key conjoint roles of Gsx2 in mediating MSN and OL second wave developmental functions, and (4) selective temporal ablation of mHtt after neural development recapitulates characteristic features of HD (EUREKA R01). Our Specific Aims are to define: (1) roles of ventrally- vs. dorsally-derived developmental OLs in HD WMT abnormalities, (2) pathogenic roles of OLs and WMT abnormalities in HD pathogenesis and therapeutic benefits of OL-based molecular genetic and cell replacement interventions. Our research approach will study: (I) differential ontogenic expression of Gsx2 in HD, (II) dynamic OL-specific lineage aberrations in HD, (III) molecular genetic rescue of Gsx2-dependent OL deficits in HD, (IV) role of HD-associated OL abnormalities in HD pathogenesis via conditional ablation of mHtt in OL precursors, (V) effects on HD onset/progression of OL cell replacement strategies. The Significance includes: (A) defining the developmental nature of HD OL lineage abnormalities, (B) establishing that a non-neuronal/non-cell autonomous mechanism is part of the pathogenic cascade leading to neuronal cell death, (C) establishing that HD represents a new class of primary developmental oligodendrogliopathy, (D) initiating entirely new directions for gene and cell based therapeutic studies during the prodromal phase based upon the HD-mediated OL developmental dysfunction. The Innovation is (1) proposing a novel mechanism underlying HD pathogenesis by incorporating a "two-hit" model including developmental forebrain OL deficits, (2) employing OL lineage-tracing to study the HD developmental oligodendrogliopathy, (3) using time-specific conditional genetic manipulations to rescue the putative HD developmental oligodendrogliopathy, (4) using cell replacement of OL developmental species to treat HD.

描述（由申请人提供）：亨廷顿病：一种新型发育性少突胶质细胞病亨廷顿病（HD）是一种持续进行性神经退行性疾病，通常表现为进行性认知/运动缺陷，尽管 HD 表现出单一的遗传基础（突变亨廷顿蛋白 [mHtt]），我们对 HD 发病机制的理解仍然不明确。HD 的标志是纹状体中棘神经元 (MSN) 的变性，因此，HD 的研究主要集中于纹状体中棘神经元 (MSN) 的退化。然而，人们越来越认识到 HD 病理学还包括少突胶质细胞 (OL)、髓磷脂和白质束 (WMT) 的功能障碍，这些缺陷发生在 HD 的前驱期。 OL 介导的机制可能在 HD 发病机制中发挥重要作用，在这里，我们检验了以下假设：出生后 WMT 异常是：（1）继发于导致第二波发育前脑少突胶质细胞生成的缺陷。第一波非髓鞘 OL 的异位持续存在，以及 (2) 前脑易受神经变性影响的区域特异性特征所必需的。这一发育假设基于我们的实验数据，显示：(1) 多个 NSC 介导的 MSN 受损。 HD 敲入小鼠模型中的发育参数，(2) HD 小鼠模型/人类病理标本中的早期和稳定的 OL 损伤，(3) Gsx2 在介导 MSN 和 OL 中的关键联合作用第二波发育功能，以及（4）神经发育后 mHtt 的选择性时间消融概括了 HD 的特征（EUREKA R01），我们的具体目标是定义：（1）腹侧与背侧衍生的发育 OL 在 HD 中的作用。 WMT 异常，(2) OL 和 WMT 异常在 HD 发病机制中的致病作用以及基于 OL 的分子遗传和细胞替代干预措施的治疗益处我们的研究方法将研究：(I)。 HD 中 Gsx2 的个体发育差异表达，(II) HD 中动态 OL 特异性谱系畸变，(III) HD 中 Gsx2 依赖性 OL 缺陷的分子遗传学拯救，(IV) HD 相关 OL 异常通过条件在 HD 发病机制中的作用OL 前体中 mHtt 的消融，(V) OL 细胞替代策略对 HD 发作/进展的影响。意义包括：(A) 定义 HD OL 谱系的发育性质。异常，(B) 确定非神经元/非细胞自主机制是导致神经元细胞死亡的致病级联的一部分，(C) 确定 HD 代表一类新的原发性发育性少突胶质细胞病，(D) 启动全新的基于 HD 介导的 OL 发育功能障碍的前驱期基因和细胞治疗研究的方向创新在于 (1) 通过纳入包括发育前脑在内的“二次打击”模型，提出了 HD 发病机制的新机制。 OL 缺陷，(2) 采用 OL 谱系追踪来研究 HD 发育性少突胶质细胞病，(3) 使用特定时间的条件基因操作来挽救假定的 HD 发育性少突胶质细胞病，(4) 使用 OL 发育物种的细胞替代来治疗 HD。