Parkinson's disease therapies targeting GUCY2C

针对 GUCY2C 的帕金森病疗法

• 批准号: 10538155
• 负责人: Lara Cheslow
• 金额: $ 4.8万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538155
• 关键词: 1-Methyl-4-phenylpyridinium; Abbreviations; Apoptosis; Autoimmunity; Body Weight; Brain; Cell Death; Cell Nucleus; Cessation of life; Chronic; Colorectal Cancer; Constipation; DNA Damage; Data; Dementia; Desire for food; Development; Disease; Disease Progression; Dopamine; Dyskinetic syndrome; Electrolyte Balance; Endocrine; FDA approved; Fluid Balance; Functional disorder; Gastrointestinal Hormone Receptors; Hormones; Human; Hyperphagia; Hypothalamic structure; In Vitro; Inflammation; Injury; Intestines; Leptin; Ligands; Limb structure; Link; MPTP Poisoning; MPTP treatment; Malignant Neoplasms; Midbrain structure; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Obesity; Oral; Outcome; Oxidative Stress; Parkinson Disease; Pharmaceutical Preparations; Physiological; Primates; Production; Reactive Oxygen Species; Respiration; Rodent; Role; Satiation; Signal Transduction; Structure; Substantia nigra structure; Symptoms; Syndrome; Therapeutic; Toxic effect; Toxin; Transgenic Mice; Translating; Translations; age related neurodegeneration; density; dopaminergic neuron; enterotoxin receptor; gut-brain axis; in vivo; mRNA Expression; mitochondrial dysfunction; motor disorder; motor symptom; novel; novel therapeutic intervention; novel therapeutics; paracrine; preservation; prevent; protein expression; receptor; reduce symptoms; targeted treatment; toxicant; transcriptome; uroguanylin

PROJECT SUMMARY/ABSTRACT Parkinson’s disease is the second most common cause of age-related neurodegeneration in the U.S. In Parkinson’s disease, mitochondrial dysfunction in midbrain dopaminergic neurons in the substantia nigra induces oxidative stress and cell death. In turn, this neurodegeneration leads to dopamine depletion, which underlies the motor dysfunction and dementia that are hallmarks of this disease. Current therapies raise dopamine levels to relieve motor symptoms, but do not prevent neurodegeneration, disease progression, or death. Thus, there is an essential unmet need to develop novel therapeutic strategies that protect dopaminergic neurons from degeneration to prevent and treat Parkinson’s disease. Guanylyl cyclase C (GUCY2C) is the intestinal receptor for the hormone uroguanylin produced in intestine, with a canonical role in fluid and electrolyte balance. In intestine, this paracrine axis supports mitochondrial structure and function, and its disruption, universally reflecting hormone loss, is central to the pathophysiology of cancer; inflammation and autoimmunity; and toxic injury. Recently, uroguanylin emerged as the afferent limb of endocrine axes controlling two discrete circuits in brain. GUCY2C in neurons in the hypothalamic ventral premamillary nucleus controls leptin signaling regulating satiety and body weight. Disrupting this gut-brain endocrine axis contributes to hyperphagia underlying obesity. Further, GUCY2C is expressed by dopaminergic neurons in the substantia nigra, although its (patho)physiological function remains undefined. Our preliminary studies reveal that silencing GUCY2C increases the vulnerability of dopaminergic neurons in the substantia nigra in mice to degeneration induced by MPTP, a mitochondrial toxin that selectively kills dopaminergic neurons in the substantia nigra in rodents, primates, and humans. Moreover, GUCY2C signaling supports the mitochondrial transcriptome central to preventing Parkinson’s disease, and silencing GUCY2C causes a significant loss of mitochondrial protein within the substantia nigra. These preliminary studies suggest a model in which the GUCY2C-uroguanylin gut-brain endocrine axis controls midbrain vulnerability to toxic insults by maintaining mitochondrial integrity to protect dopaminergic neurons in the substantia nigra. Thus, studies here explore the novel Physiological Hypothesis that uroguanylin secreted by intestine and GUCY2C expressed in the midbrain form a novel endocrine gut-brain axis that protects dopaminergic neurons, opposing toxic degeneration. The Mechanistic Hypothesis suggests that GUCY2C protects the integrity of midbrain dopaminergic neurons by supporting mitochondrial structure and function. The Therapeutic Hypothesis suggests that exogenous GUCY2C ligands protect midbrain dopaminergic neurons from toxic insults, potentially opposing the development and progression of Parkinson’s disease. The possibility of translating these studies into new therapeutic strategies to prevent and treat Parkinson’s disease can be appreciated by considering that the GUCY2C ligands linaclotide (Linzess™) and plecanatide (Trulance™) are FDA-approved to treat chronic constipation syndromes.

项目摘要/摘要 帕金森氏病是美国第二大最常见的与年龄有关的神经变性原因 帕金森氏病，中脑多巴胺能神经元的线粒体功能障碍，Nigra诱导 氧化应激和细胞死亡。反过来，这种神经变性导致多巴胺耗竭，这是 运动功能障碍和痴呆症是该疾病的标志。当前疗法将多巴胺水平提高到 缓解运动症状，但不能预防神经变性，疾病进展或死亡。那是 制定新型治疗策略的必需需求，以保护多巴胺能神经元免受 预防和治疗帕金森氏病的变性。 Guanylyl Cyclase C（Gucy2c）是肠接收器 对于在肠道中产生的马龙泌尿鸟蛋白，在液体和电解质平衡中具有典型的作用。 肠道，该旁分泌轴支持线粒体的结构和功能，其破坏是普遍的 反映马龙丧失是癌症病理生理学的核心。感染和自身免疫性；和有毒 受伤。最近，泌尿原蛋白作为控制两个离散电路的内分泌轴的传入四肢 脑。下丘脑腹膜前核中神经元中的gucy2c控制瘦素信号传导调节 饱腹感和体重。破坏这种肠道内分泌轴有助于肥胖的肥大。 此外，gucy2c在黑质中由多巴胺能神经元表达，尽管它 （PATHO）生理功能仍然不确定。我们的初步研究表明，沉默的Gucy2c 增加小鼠黑质中多巴胺能神经元的脆弱性，从 MPTP是一种线粒体毒素，在啮齿动物的斑nigra中有选择地杀死多巴胺能神经元， 灵长类动物和人类。此外，gucy2c信号传导支持中心的线粒体转录组 防止帕金森氏病，并使Gucy2c沉默会在内部显着丧失线粒体蛋白 黑质尼格拉。这些初步研究提出了一个模型，其中gucy2c-尿素蛋白肠脑脑 内分泌轴通过维持线粒体完整性来保护中脑对有毒侮辱的脆弱性 黑质的多巴胺能神经元。在这里，研究探讨了新的生理假设 用肠和gucy2c在中脑中表达的那种泌尿鸟蛋白蛋白形成了一种新型内分泌肠脑 保护多巴胺能神经元的轴，反对毒性变性。机械假设表明 Gucy2c通过支持线粒体结构和 功能。治疗假设表明，外源Gucy2c配体保护中脑 来自毒性感染的多巴胺能神经元可能反对帕金森氏症的发展和发展 疾病。将这些研究转化为预防和治疗的新治疗策略的可能性 帕金森氏病可以考虑到Gucy2C​​ Ligands linaclotide（Linzess™）和 Plecanatide（Trulance™）经FDA批准以治疗慢性便秘综合征。