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 帕金森氏症是美国与年龄相关的神经变性的第二大常见原因。 帕金森病，中脑黑质多巴胺能神经元线粒体功能障碍 氧化应激和细胞死亡。反过来，这种神经退行性变导致多巴胺耗竭，这是 运动功能障碍和痴呆症是这种疾病的特征。目前的治疗方法将多巴胺水平提高到 缓解运动症状，但不能防止神经退化、疾病进展或死亡。因此，有 开发新的治疗策略以保护多巴胺能神经元免受 预防和治疗帕金森氏症的退化症。鸟苷酸环化酶C(GUCY2C)是肠道受体 对于肠道中产生的荷尔蒙尿鸟苷，具有调节水电解质平衡的规范作用。在……里面 肠，这个旁分泌轴支持线粒体的结构和功能，以及它的破坏，普遍 反映荷尔蒙丢失，是癌症、炎症和自身免疫以及毒性的病理生理学的中心 受伤。最近，尿鸟苷作为内分泌轴的传入肢体出现，控制着两个独立的回路。 大脑。下丘脑腹侧乳房前核神经元GUCY2C控制瘦素信号调控 饱腹感和体重。破坏这一肠道-大脑内分泌轴会导致肥胖的吞噬过度。 此外，GUCY2C由黑质中的多巴胺能神经元表达，尽管其 (病理)生理功能仍未确定。我们的初步研究表明，让GUCY2C保持沉默 增加小鼠黑质多巴胺能神经元对小鼠黑质变性的易感性 MPTP是一种线粒体毒素，可以选择性地杀死啮齿动物黑质中的多巴胺能神经元， 灵长类动物和人类。此外，GUCY2C信号支持线粒体转录组的中心 预防帕金森氏症和沉默GUCY2C会导致体内线粒体蛋白的显著损失 黑质。这些初步研究提出了一种模型，在该模型中，GUC2C-尿鸟苷肠-脑 内分泌轴通过保持线粒体完整性来保护中脑对毒物伤害的易感性 黑质内的多巴胺能神经元。因此，这里的研究探索了新的生理学假说 肠道分泌的尿鸟苷和中脑表达的GUCY2C形成了一种新的内分泌肠脑 轴，保护多巴胺能神经元，反对毒性退化。力学假说表明 GUCY2C通过支持线粒体结构和保护中脑多巴胺能神经元的完整性 功能。治疗假说表明外源性GUCY2C配体保护中脑 来自有毒侮辱的多巴胺能神经元，潜在地对抗帕金森病的发生和发展 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 帕金森病可以通过考虑GUCY2C配体linacloide(linzess™)和 普来卡那肽(Trulance™)是美国食品和药物管理局批准的用于治疗慢性便秘综合征的药物。