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.

项目总结/摘要 帕金森病是美国年龄相关性神经退行性疾病的第二大常见原因。 帕金森病，黑质中脑多巴胺能神经元线粒体功能障碍诱导 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是这种疾病的标志。目前的治疗方法提高多巴胺水平， 缓解运动症状，但不能防止神经变性、疾病进展或死亡。因此， 开发新的治疗策略以保护多巴胺能神经元免受 预防和治疗帕金森病。鸟苷酸环化酶C（GUCY 2C）是肠道受体 肠内产生的激素尿鸟苷素，在体液和电解质平衡中具有典型作用。在 肠，这旁分泌轴支持线粒体的结构和功能，其破坏，普遍 反映激素损失，是癌症病理生理学的核心;炎症和自身免疫;和毒性 损伤最近，尿鸟苷素作为内分泌轴的传入分支出现，控制两个离散回路， 个脑袋下丘脑腹侧乳头前核神经元GUCY 2C调控瘦素信号转导 饱腹感和体重。破坏这一肠-脑内分泌轴有助于引起肥胖症的暴食症。 此外，GUCY 2C由黑质中的多巴胺能神经元表达，尽管它的表达与黑质中的多巴胺能神经元的表达无关。 （病理）生理功能仍然不明确。我们的初步研究表明，沉默GUCY 2C 增加了小鼠黑质中多巴胺能神经元对 MPTP是一种选择性杀死啮齿动物黑质多巴胺能神经元的线粒体毒素， 灵长类动物和人类此外，GUCY 2C信号支持线粒体转录组中心， 预防帕金森病，沉默GUCY 2C会导致线粒体蛋白质的显著损失， 黑质这些初步研究表明，在模型中，GUCY 2C-尿鸟苷素肠-脑 内分泌轴通过维持线粒体完整性来控制中脑对毒性损伤的脆弱性， 黑质的多巴胺能神经元因此，这里的研究探讨了新的生理假说 肠分泌的尿鸟苷素和中脑表达的GUCY 2C形成了一种新的内分泌肠-脑 轴，保护多巴胺能神经元，对抗毒性变性。机械论假说认为 GUCY 2C通过支持线粒体结构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GUCY 2C配体保护中脑 多巴胺能神经元免受毒性损伤，可能对抗帕金森病的发展和进展 疾病将这些研究转化为新的治疗策略以预防和治疗 帕金森病可以通过考虑GUCY 2C配体利那洛肽（Linzess™）和利那洛肽（Linzess™）来理解。 Plecanlide（Trulance™）是FDA批准用于治疗慢性便秘综合征的。