The role of gut endocrine cells in Parkinson's Disease

肠道内分泌细胞在帕金森病中的作用

基本信息

批准号：
9756369
负责人：
Rodger A. Liddle
金额：
$ 35.78万
依托单位：
DUKE UNIVERSITY
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：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756369
关键词：
Apical Axon Brain Brain Diseases Cell Surface Receptors Cells Communication Data Digestion Disease Eating Enteral Enterocytes Enteroendocrine Cell Environment Environmental Exposure Epidemiology Epithelial Cells Exposure to Food Future Gastrointestinal tract structure Gut Mucosa Herbicides Ingestion Injury Intestines Lewy Bodies Molecular Nervous system structure Neurodegenerative Disorders Neurons Paraquat Parkinson Disease Pathogenesis Pathway interactions Patients Pesticides Process Proteins Rabies virus Role Rotenone Secretory Vesicles Sensory Signal Transduction Source Surface Synapses Synaptic Vesicles Testing Tissues Toxicant exposure alpha synuclein gastrointestinal epithelium gut endocrine cell insight neurofilament novel pathogen presynaptic neurons prion-like protein aggregate public health relevance relating to nervous system toxicant vesicular release

项目摘要

DESCRIPTION (provided by applicant): Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Their apical surface is open to the lumen of the intestine and their basolateral surface contains abundant secretory vesicles that are released upon stimulation of the cell. Through specific cell surface receptors, EECs sense food as it passes through the intestine. We recently discovered that EECs of the gut possess many neuron-like features including axon-like processes known as neuropods. It is through neuropods that EECs connect to neurons. This neural connection provides a direct communication from the gut to the brain and is how the brain senses luminal contents. The gastrointestinal tract is constantly exposed to the environment through food that sometimes harbors herbicides and pesticides and EECs in the gut mucosa are ready targets for herbicide exposure. Epidemiological and experimental data indicate that environmental exposure to herbicides and pesticides is a major cause of Parkinson's disease. Parkinson's disease is characterized by intraneuronal Lewy bodies that consist of aggregates of α-synuclein, a neuronal protein that may protect against toxic injury. Aggregates of α-synuclein can be passed from cell to cell, inducing aggregates in a "prion-like cascade" that spreads through the nervous system. Abnormal α-synuclein appears in enteric neurons before it spreads to the brain. Therefore, Parkinson's disease arises in regions where neural tissues are in close proximity to the environment, such as the gut, although how this occurs is unknown. Among their neuron-like features we discovered that EECs also express α-synuclein. This finding raises the possibility that EECs are the source of Parkinson's disease. We propose that pesticides and herbicides cause abnormal α-synuclein in EECs that is transmitted to neurons in the gut and spreads to the nervous system. We will test this hypothesis by determining if herbicides and pesticides known to cause Parkinson's disease produce abnormal α-synuclein in EECs and if EECs transmit is folded α-synuclein to neurons. These studies will determine if EECs are the source of abnormal α-synuclein that could be the origin of Parkinson's disease. Identifying the source of Parkinson's disease may offer new targets for future therapy.

描述（申请人提供）：肠内分泌细胞（EEC）是胃肠道的感觉细胞，其顶端表面向肠腔开放，其基底外侧表面含有丰富的分泌囊泡，这些囊泡在细胞受到特定刺激时释放。细胞表面受体，EEC 在食物通过肠道时感知食物，我们最近发现肠道的 EEC 具有许多类似神经元的特征，包括。 EEC 通过神经突连接到神经元，这种神经连接提供了从肠道到大脑的直接通信，并且是大脑通过胃肠道不断暴露于环境的方式。有时含有除草剂和杀虫剂的食物以及肠道粘膜中的 EEC 是除草剂暴露的现成目标。流行病学和实验数据表明，环境接触除草剂和杀虫剂是一个主要原因。帕金森病的特征是神经元内路易体由 α-突触核蛋白聚集体组成，α-突触核蛋白聚集体可以在细胞之间传递，从而诱导“朊病毒”聚集。异常的α-突触核蛋白在扩散到大脑之前会出现在神经系统中，因此，帕金森病会出现在神经系统的区域。在与环境非常接近的组织中，例如肠道，在它们的神经元样特征中，我们发现 EEC 也表达 α-突触核蛋白，这一发现提出了 EEC 是帕金森病的根源的可能性。我们提出杀虫剂和除草剂会导致 EEC 中的异常 α-突触核蛋白传播到肠道神经元并扩散到神经系统。我们将通过确定除草剂和杀虫剂是否已知会导致这种现象来检验这一假设。帕金森病在 EEC 中产生异常的 α-突触核蛋白，如果 EEC 将折叠的 α-突触核蛋白传递给神经元，这些研究将确定 EEC 是否是异常 α-突触核蛋白的来源，从而确定帕金森病的根源。可能为未来的治疗提供新的靶点。