Neuroprotection by the GUCY2C gut-brain axis in Parkinson's disease

GUCY2C 肠脑轴对帕金森病的神经保护作用

基本信息

  • 批准号:
    10740951
  • 负责人:
  • 金额:
    $ 42.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Parkinson’s disease (PD) is the second most common cause of age-related neurodegeneration in the U.S. In PD, mitochondrial dysfunction in midbrain dopamine (DA) neurons in the substantia nigra (SN) induces oxidative stress and cell death. In turn, this neurodegeneration leads to DA depletion, which underlies the motor dysfunction and dementia that are hallmarks of this disease. Current therapies raise DA 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 DA neurons from degeneration to prevent and treat PD. Guanylyl cyclase C (GUCY2C) is an intestinal receptor for locally-produced hormones that regulate secretion, the basis for approval of the GUCY2C agonist linaclotide to treat constipation. In intestine, this receptor signaling axis also supports mitochondrial biogenesis through the transcriptional coactivator PGC1α, and its disruption produces mitochondrial dysfunction central to the pathophysiology of cancer; inflammatory bowel disease; and toxic injury. Recently, the GUCY2C hormone axis emerged as the afferent limb of endocrine pathways controlling two discreet circuits in brain. GUCY2C in neurons in the hypothalamic ventral premammillary nucleus controls leptin signaling regulating appetite. Disrupting this gut-brain endocrine axis contributes to hyperphagia underlying obesity. Further, GUCY2C is expressed by DA neurons in the SN, where it plays a role in memory and behavior. Our preliminary studies suggest that GUCY2C supports mitochondrial biogenesis protecting DA neurons in the SN from toxic insults. Thus, silencing GUCY2C amplifies DA neuron degeneration in the SN induced by MPTP, a mitochondrial toxin that selectively kills DA neurons. This DA neuron toxicity is associated with depletion of DA and its metabolites from the striatum, and induction of inflammation and reactive gliosis in the SN. Moreover, silencing GUCY2C in DA neurons depletes mitochondria, and their associated electron transport complexes, from the SN, characteristic of toxic insults in PD. These preliminary studies suggest a model in which the GUCY2C-signaling axis controls midbrain vulnerability to toxic insults by supporting mitochondrial biogenesis protecting DA neurons in the SN. Studies here explore two novel hypotheses. The Therapeutic Hypothesis suggests that toggling GUCY2C in the midbrain “OFF” (genetically), or “ON” (linaclotide stimulation) modulates the vulnerability of DA neurons to toxic degeneration. The Mechanistic Hypothesis suggests that GUCY2C protects the integrity of SN DA neurons through PGC1α- dependent mitochondrial biogenesis. These studies will reveal a therapeutic target (midbrain GUCY2C), a mechanism (mitochondrial biogenesis) that may be generalizable to the spectrum of toxic insults in the midbrain, and a specific therapeutic paradigm (linaclotide) to prevent midbrain DA neurodegeneration. The potential to translate these studies into new strategies to prevent and treat PD can best be appreciated by considering that the GUCY2C agonists linaclotide and plecanatide are FDA-approved to treat chronic constipation syndromes.
帕金森氏病(PD)是美国与年龄相关的神经退行性的第二常见原因 PD,中脑多巴胺(DA)神经元中的线粒体功能障碍(SN)诱导氧化 压力和细胞死亡。反过 功能障碍和痴呆症是该疾病的标志。当前疗法提高了DA水平来挽救电动机 症状,但不能预防神经退行性,疾病进展或死亡。那是必不可少的 未满足的需要开发新型的治疗策略,以保护DA神经元免受预防和预防的变性 治疗PD。 Guanylyl Cyclase C(GuCy2C)是用于调节局部生产的激素的肠接收器 分泌,批准Gucy2c激动剂linaclotide来治疗便秘的基础。在肠中,这个接收器 信号轴还通过转录共激活因子PGC1α支持线粒体生物发生及其。 破坏会导致癌症病理生理学中心的线粒体功能障碍。炎症性肠 疾病;和有毒伤害。最近,Gucy2c激素轴成为内分泌的传入肢 控制大脑中两个谨慎电路的途径。下丘脑腹神经元中的gucy2c 牙后核控制着瘦素信号传导调节食欲。破坏这个肠道内分泌轴 有助于肥胖的肥大。此外,gucy2c在SN中由DA神经元表示 它在记忆和行为中起作用。我们的初步研究表明,GuCy2c支持线粒体 生物发生保护SN中的DA神经元免受毒性感染。那是沉默的gucy2c放大器da神经元 MPTP诱导的SN的变性,MPTP是一种有选择地杀死DA神经元的线粒体毒素。这个da神经元 毒性与纹状体的DA及其代谢产物的耗竭以及炎症诱导有关 和SN中的反应性神经病。此外,在DA神经元中沉默的Gucy2c耗尽了线粒体及其 相关的电子传输复合物,来自SN,PD中有毒感染的特征。这些初步 研究提出了一个模型,其中GuCy2C信号轴控制了中脑脆弱性对有毒感染的脆弱性 支持线粒体生物发生保护SN中的DA神经元。这里的研究探索了两本小说 假设。治疗假设表明,在中脑“ OFF”(遗传上)中切换Gucy2c, 或“ ON”(Linaclotide刺激)调节DA神经元对毒性变性的脆弱性。这 机械假设表明,GuCy2c通过PGC1α-保护Sn DA神经元的完整性 依赖性线粒体生物发生。这些研究将揭示一个治疗靶标(中脑Gucy2c),一个 机理(线粒体生物发生)可能可以推广到中脑中有毒感染的光谱, 和特定的热范式(Linaclotide),以防止中脑DA神经变性。潜力 将这些研究转化为预防和治疗PD的新策略,可以通过考虑到 Gucy2c激动剂Linaclotide和Plecanatide经FDA批准以治疗慢性便秘综合征。

项目成果

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SCOTT A WALDMAN其他文献

SCOTT A WALDMAN的其他文献

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{{ truncateString('SCOTT A WALDMAN', 18)}}的其他基金

Guanylin GUCY2C axis in Colorectal Cancer Initiation
鸟苷素 GUCY2C 轴在结直肠癌发生中的作用
  • 批准号:
    9237630
  • 财政年份:
    2017
  • 资助金额:
    $ 42.9万
  • 项目类别:
(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation
(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化
  • 批准号:
    9922880
  • 财政年份:
    2016
  • 资助金额:
    $ 42.9万
  • 项目类别:
(PQ1) GUCY2C hormone loss translates APC-Beta-catenin mutations into epithelial transformation
(PQ1)GUCY2C激素损失将APC-β-连环蛋白突变转化为上皮转化
  • 批准号:
    9101320
  • 财政年份:
    2016
  • 资助金额:
    $ 42.9万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8680189
  • 财政年份:
    2012
  • 资助金额:
    $ 42.9万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8517056
  • 财政年份:
    2012
  • 资助金额:
    $ 42.9万
  • 项目类别:
GUCY2C hormone signaling at the intersection of obesity and colorectal cancer(PQ1
肥胖与结直肠癌交叉点上的 GUCY2C 激素信号传导(PQ1
  • 批准号:
    8895861
  • 财政年份:
    2012
  • 资助金额:
    $ 42.9万
  • 项目类别:
Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
  • 批准号:
    7828432
  • 财政年份:
    2009
  • 资助金额:
    $ 42.9万
  • 项目类别:
Occult lymph node metastases and racial disparities in colon cancer outcomes
结肠癌结果中的隐匿性淋巴结转移和种族差异
  • 批准号:
    7941015
  • 财政年份:
    2009
  • 资助金额:
    $ 42.9万
  • 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
  • 批准号:
    6772420
  • 财政年份:
    2003
  • 资助金额:
    $ 42.9万
  • 项目类别:
Guanylyl Cyclase C in Blood and Colorectal Cancer
血液和结直肠癌中的鸟苷酸环化酶 C
  • 批准号:
    6685481
  • 财政年份:
    2003
  • 资助金额:
    $ 42.9万
  • 项目类别:

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卡芬太尼引起呼吸系统疾病及死亡的机制及对策
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  • 批准号:
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Targeting visceral pain through intestinal neuropod cell GUCY2C signaling
通过肠道神经足细胞 GUCY2C 信号传导治疗内脏疼痛
  • 批准号:
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