Administrative Supplement to Molecular Segregation of Parkinson’s Disease by Patient-derived Neurons

患者来源神经元对帕金森病分子分离的行政补充

基本信息

批准号：
10709193
负责人：
JIAN FENG
金额：
$ 40.13万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709193
关键词：
Address Administrative Supplement Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Autopsy Benchmarking Biological Markers Biological Models Brain California Clinical Cognitive Cognitive deficits Complex Dementia Dementia with Lewy Bodies Developmental Biology Disease Dopamine Exhibits Foundations Freezing Future Gene Expression Gene Expression Profile Genes Grant Human Idiopathic Parkinson Disease Lewy Bodies Lewy Body Dementia Lewy Body Disease Lewy neurites Measures Medial Memory Memory impairment Methods Midbrain structure Molecular National Institute of Neurological Disorders and Stroke Neuronal Differentiation Neurons Parkinson Disease Parkinson&apos s Dementia Patients Phosphorylation Regenerative Medicine Substantia nigra structure Synapses Temporal Lobe Testing Tissues United States National Institutes of Health Western Blotting age related brain tissue cell repository cohort comorbidity data repository disease diagnosis dopaminergic neuron drug discovery endophenotype induced pluripotent stem cell motor symptom neuron loss neuropathology programs segregation sex synuclein tau-1 transcriptome transcriptome sequencing

项目摘要

Summary Dementia is an age-dependent co-morbidity of Parkinson’s disease (PD) that affects up to 80% of PD patients. There is very little mechanistic understanding of PD Dementia (PDD), which together with Dementia with Lewy Body (DLB), constitute Lewy Body Dementia (LBD). The lack of a suitable model system significantly hampers the study of this complex disorder, which shares many features with Alzheimer’s disease (AD). In our preliminary study, we developed a method to differentiate induced pluripotent stem cells (iPSCs) to cortical neurons. Comparing cortical neurons derived from normal subjects and sporadic Alzheimer’s disease patients, we found significant increases in TAU phosphorylation and significant decreases in the expression of synaptic genes. In our parental R01 grant, we have developed a method to differentiate iPSCs to A9 dopaminergic (DA) neurons. In midbrain DA neurons derived from normal subjects and idiopathic PD patients, we have found significant differences in the expression of genes handling dopamine. Premised on these findings, we hypothesize that iPSC-derived cortical neurons and A9 dopaminergic neurons from LBD patients may exhibit molecular and cellular features that are significantly different from those of normal subjects. Three specific aims will be addressed to test the hypothesis, which extends the parental R01 grant to dementia in this administrative supplement application. We will generate cortical neurons (Aim 1) and A9 DA neurons (Aim 2) from iPSCs of LBD patients and normal subjects to examine the phosphorylation and aggregation states of TAU and -synuclein, and compare the global gene expression profile. We will confirm key findings in postmortem tissues from middle temporal cortex and substantia nigra of LBD patients and normal subjects (Aim 3). Information generated in this focused study will lay the foundation for discovery of LBD biomarkers using patient-derived neurons. Key targets identified in the study can be validated in drug discovery efforts to address cognitive, memory and motor symptoms of LBD using patient-derived cortical neurons or A9 DA neurons. The administrative supplement application will move the field forward by identifying molecular and cellular features that distinguish LBD from normal subjects in patient-derived neurons and postmortem tissues.

概括痴呆症是帕金森病 (PD) 的一种年龄依赖性合并症，影响高达 80% 的 PD 患者对 PD 痴呆 (PDD) 的机制了解甚少，它与路易体痴呆（DLB）一起构成路易体痴呆（LBD）。缺乏合适的模型系统极大地阻碍了对这种复杂疾病的研究，在我们的初步研究中，它与阿尔茨海默病（AD）有许多共同特征。开发了一种将诱导多能干细胞（iPSC）分化为皮质神经元的方法。比较来自正常受试者和散发性阿尔茨海默氏病的皮层神经元患者中，我们发现 TAU 磷酸化显着增加，而在我们的亲本 R01 资助中，我们开发了一种方法来表达突触基因。将 iPSC 分化为源自中脑 DA 神经元的 A9 多巴胺能 (DA) 神经元。正常受试者和特发性PD患者，我们发现在以这些发现为前提，我们发现了处理多巴胺的基因的表达。来自 LBD 患者的 iPSC 衍生的皮质神经元和 A9 多巴胺能神经元可能表现出分子和细胞特征与正常受试者显着不同。将解决三个具体目标来检验该假设，该假设扩展了父母 R01 在此行政补充申请中，我们将生成大脑皮层的痴呆症补助金。来自 LBD 患者和正常受试者 iPSC 的神经元（目标 1）和 A9 DA 神经元（目标 2）检查 TAU 和 α-synuclein 的磷酸化和聚集状态，并比较我们将确认死后组织中的关键发现。 LBD 患者和正常受试者的颞叶皮质和黑质（目标 3）。这项重点研究中产生的结果将为使用 LBD 生物标记物的发现奠定基础研究中确定的患者来源的神经元可以在药物发现中得到验证。使用患者来源的皮质来解决 LBD 的认知、记忆和运动症状神经元或 A9 DA 神经元的行政补充应用程序将推动该领域的发展。通过识别区分 LBD 和正常受试者的分子和细胞特征来向前推进在患者来源的神经元和死后组织中。