The developmental basis of dopaminergic neuron diversity

多巴胺能神经元多样性的发育基础

• 批准号: 8472547
• 负责人: Rajeshwar B Awatramani
• 金额: $ 18.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472547
• 关键词: Accounting; Anterior; Attention; Axon; Behavior; Biogenesis; Birth; Candidate Disease Gene; Cell Nucleus; Cell Therapy; Development; Disease; Dopamine; Dorsal; Dystonia; Embryo; Enzymes; Erinaceidae; Event; Floor; Gene Expression; Genetic; Heterogeneity; Lateral; Link; Location; Maps; Medial; Midbrain structure; Modeling; Molecular Profiling; Movement; Mus; Neurons; Organism; Parkinson Disease; Patients; Pattern; Physiological; Population; Predisposition; Primordium; Rewards; Schizophrenia; Scientist; Series; Stem cells; Subgroup; Substantia nigra structure; System; Testing; Time; Tracer; Tretinoin; Ventral Tegmental Area; base; cell fate specification; dopamine system; dopaminergic neuron; induced pluripotent stem cell; morphogens; motor deficit; pars compacta; progenitor; research study; tool

DESCRIPTION (provided by applicant): The drastic motor deficit in Parkinson's disease (PD) patients is largely caused by a substantial loss of midbrain dopamine neurons (mDA). Careful morphometric studies have revealed a selective susceptibility of certain mDA populations. Thus, mDA neurons found in the ventral tier of the substantia nigra pars compacta (SNpc; A9) are more vulnerable, compared to mDA located in the dorsal tier of the SNpc, or in the Ventral Tegmental Area (A10). This differential susceptibility highlights the diversity of mDA populations. We hypothesize that in the developing midbrain, there are multiple distinct mDA progenitor pools, each of which gives rise to distinct mDA subtypes. We will attempt to determine the progenitor pool for the most susceptible type of dopamine neuron in PD. Accordingly, we will lineage trace one proposed mDA progenitor pool and determine whether its descendents populate the most vulnerable regions of the dopaminergic field i.e. the ventral tier of the SNpc. Next we will develop topographic maps for this DA subtype. Together, these experiments will provide a first glimpse into how mDA diversity is generated. Elucidating the developmental basis for this diversity will be critical for understanding differential susceptibility of mDA, as well as generating accurate ES or iPSC stem cell derived models and therapies for PD.

描述（由申请人提供）：帕金森病（PD）患者的剧烈运动缺陷很大程度上是由中脑多巴胺神经元（mDA）的大量损失引起的。仔细的形态测量研究揭示了某些 mDA 群体的选择性易感性。因此，与位于 SNpc 背层或腹侧被盖区 (A10) 的 mDA 相比，在黑质致密部 (SNpc; A9) 腹侧层发现的 mDA 神经元更脆弱。这种不同的易感性凸显了 mDA 群体的多样性。我们假设，在发育中的中脑中，存在多个不同的 mDA 祖细胞池，每个祖细胞池都会产生不同的 mDA 亚型。我们将尝试确定 PD 中最易受影响的多巴胺神经元类型的祖细胞池。因此，我们将谱系追踪一个拟议的 mDA 祖细胞池，并确定其后代是否分布在多巴胺能场最脆弱的区域，即 SNpc 的腹侧层。接下来我们将为这个 DA 子类型开发地形图。总之，这些实验将让我们初步了解 mDA 多样性是如何产生的。阐明这种多样性的发育基础对于理解 mDA 的差异易感性以及生成准确的 ES 或 iPSC 干细胞衍生模型和 PD 疗法至关重要。