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.

概括痴呆是帕金森氏病（PD）的依赖年龄的合并症到80％的PD患者。对PD痴呆（PDD）的机械理解很少，与痴呆症与Lewy身体（DLB）一起，构成Lewy身体痴呆症（LBD）。缺乏合适的模型系统会显着阻碍对这种复杂疾病的研究，与阿尔茨海默氏病（AD）具有许多特征。在我们的初步研究中，我们开发了一种将诱导多能干细胞（IPSC）与皮质神经元区分开的方法。比较源自正常受试者和零星阿尔茨海默氏病的皮质神经元患者，我们发现tau磷酸化显着增加，并且显着下降突触基因的表达。在我们的父母R01赠款中，我们开发了一种方法将IPSC与A9多巴胺能（DA）神经元区分开。在中脑da神经元中正常受试者和特发性PD患者，我们发现处理多巴胺的基因的表达。以这些发现为前提，我们假设 LBD患者的IPSC衍生的皮质神经元和A9多巴胺能神经元可能会表现出来分子和细胞特征与正常受试者的特征显着不同。将解决三个特定目标以检验该假设，该假设扩展了父母R01 在此行政补充申请中授予痴呆症。我们将生成皮质 LBD患者IPSC和正常受试者的神经元（AIM 1）和A9 DA神经元（AIM 2）检查tau和-核蛋白的磷酸化和聚集态，并比较全局基因表达谱。我们将在中间的验尸组织中确认关键发现 LBD患者和正常受试者的临时皮层和黑质（AIM 3）。信息在这项重点研究中产生的将为发现LBD生物标志物的基础患者衍生的神经元。可以在药物发现中验证研究中确定的主要目标使用患者衍生的皮质来解决LBD的认知，记忆和运动症状的努力神经元或A9 DA神经元。行政补充申请将移动该领域通过识别将LBD与正常受试者区分开的分子和细胞特征在患者来源的神经元和验尸组织中。