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Substance P tachykininergic NK1 receptor emetic signal transduction pathways

P物质速激能NK1受体催吐信号转导途径

基本信息

批准号：
10224743
负责人：
NISSAR A DARMANI
金额：
$ 30.67万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224743
关键词：
Acute Antiemetics Bacterial Infections Behavioral Biochemical Brain Stem Calcium Cancer Patient Cell membrane Cells Central Nervous System Neoplasms Cisplatin Clinic Clinical Communities Data Development Diglycerides Disease Dose Economic Burden Emetics Enterochromaffin Cells Exhibits Food Poisoning Fright Gastrointestinal Diseases Gastrointestinal tract structure Glycogen Synthase Kinase 3 Goals HIV HTR3A gene Hospitals Image Immunohistochemistry In Vitro Inositol Knowledge Lead Malignant Neoplasms Mediating Mediator of activation protein Modeling Motion Sickness Nausea and Vomiting Opioid Outcome Pathway interactions Patient Noncompliance Patients Peripheral Pharmaceutical Preparations Pharmacology Phospholipase C Play Pregnancy Prevention Protein Kinase C Protein-Serine-Threonine Kinases Quality of life Receptor Activation Regimen Research Role Serine/Threonine Phosphorylation Serotonin Serotonin Receptors 5-HT-3 Shrews Signal Transduction Signal Transduction Pathway Signaling Molecule Small Intestines Substance P Substance P Receptor Symptoms System Tachykinin Techniques Testing Therapeutic Time Tissues Treatment Cost Virus Diseases Visit Vomiting Western Blotting base behavioral pharmacology calmodulin-dependent protein kinase II compliance behavior cost cytotoxic extracellular gastrointestinal health care service improved inhibitor/antagonist insight interdisciplinary approach pill pre-clinical research prophylactic receptor side effect symptom treatment virtual

项目摘要

Acute (day 1) and delayed (days 3-7) nausea and vomiting are the feared and debilitating side-effects of cancer therapeutics such as cisplatin. In the absence of prophylactic therapy, nearly all patients vomit from cisplatin-like drugs. These side-effects must be controlled to maintain patient compliance and quality of life. However, the cost of the best antiemetic regimen (Akynzeo) containing a serotonin 5-HT3 receptor (5-HT3R) antagonist and a substance P (SP) neurokinin NK1 receptor (NK1R)-antagonist is over $500 per pill in the USA and can only protect up to 80% of patients. Cisplatin-like drugs release serotonin (5-HT) and SP which stimulate their corresponding cell membrane-bound extracellular emetic receptors in both the gut and brainstem emetic loci to evoke vomiting. Of critical importance to this application, major gaps exist in the emesis field in that there is a lack of understanding of i) activation of emetic intracellular signaling mechanisms following stimulation of discussed emetic receptors; and ii) whether potential point(s) of signal convergence (e.g. Ca2+) exist among diverse emetic signaling cascades. As new cancer therapeutics are being developed, it becomes vital that we define shared fundamental intracellular signaling molecules that underlie induction of emesis versus cancer suppression, so that we can develop safer cancer therapeutics without emesis, which will save time, effort and research dollars. Although the emetic signaling cascade(s) downstream of NK1R remain unknown, we recently have identified the intracellular 5-HT3R emetic cascade [17,18]. Unlike the narrow-spectrum 5-HT3R blockers, NK1R antagonists exhibit broad-spectrum antiemetic efficacy against diverse causes of vomiting. Thus, a full understanding of NK1R emetic signals may allow us to identify unique intracellular signal(s) whose antagonists/inhibitors would suppress cancer formation without vomiting. Indeed, SP via NK1Rs plays a central role in the development of CNS tumors and its corresponding antagonists possess cancer chemotherapeutic potential [15,16]. Furthermore, our preliminary data strongly suggest that the phospholipase C (PLC) cascade and its interaction with the Akt/GSK-3aβ pathway are major players in NK1R-evoked vomiting. The purpose of this application is to take a broad approach involving pharmacological, behavioral, calcium imaging, immunohistochemical and Western blot techniques, to delineate the NK1R-mediated emetic signal transduction involving activation of phospholipase C and corresponding downstream signals including the role of extracellular Ca2+ influx and intracellular Ca2+ release in vomiting, as well as whether the evoked emesis can be modulated by the Akt/GSK-3αβ pathway. Not only there is scant information regarding intracellular mechanisms of emesis, but also there is an urgent and unmet need for alternative broad-spectrum antiemetics for protection of all cancer patients suffering from vomiting caused by cytotoxic chemotherapeutics. The findings of this proposal will introduce not only several new highly potent classes of antiemetics, but may also help reveal the potential of universal antiemetics, which will lower the cost of prevention of nausea and vomiting in diverse patient communities suffering from cancer, HIV or gastrointestinal disorders.

急性（第1天）和延迟（第3-7天）恶心和呕吐是癌症治疗（如顺铂）的可怕和使人衰弱的副作用。在没有预防性治疗的情况下，几乎所有的患者都会因顺铂类药物而呕吐。必须控制这些副作用，以维持患者的依从性和生活质量。然而，在美国，含有5-羟色胺5-HT 3受体（5-HT 3R）拮抗剂和P物质（SP）神经激肽NK 1受体（NK 1 R）拮抗剂的最佳止吐方案（Akynzeo）的成本超过每片500美元，只能保护80%的患者。顺铂类药物释放5-羟色胺（5-HT）和SP，刺激肠和脑干呕吐部位中相应的细胞膜结合的细胞外呕吐受体，引起呕吐。对于该应用至关重要的是，在呕吐领域中存在主要的差距，因为缺乏对i）在刺激所讨论的呕吐受体之后呕吐细胞内信号传导机制的激活;和ii）在不同的呕吐信号传导级联中是否存在信号会聚的潜在点（例如Ca 2+）的理解。随着新的癌症治疗方法的开发，我们定义共同的基本细胞内信号分子变得至关重要，这些分子是诱导呕吐与抑制癌症的基础，这样我们就可以开发更安全的癌症治疗方法，而不会呕吐，这将节省时间，精力和研究资金。虽然NK 1 R下游的催吐信号级联仍然未知，但我们最近已经鉴定了细胞内5-HT 3R催吐级联[17，18]。与窄谱5-HT 3R阻断剂不同，NK 1 R拮抗剂对多种呕吐原因表现出广谱止吐功效。因此，对NK 1 R催吐信号的充分理解可能使我们能够鉴定独特的细胞内信号，其拮抗剂/抑制剂将抑制癌症形成而不呕吐。事实上，SP通过NK 1 R在CNS肿瘤的发展中起着重要作用，其相应的拮抗剂具有癌症化疗潜力[15，16]。此外，我们的初步数据强烈表明，磷脂酶C（PLC）级联及其与Akt/GSK-3aβ通路的相互作用是NK 1 R诱发呕吐的主要参与者。本申请的目的是采用涉及药理学、行为学、钙成像、免疫组织化学和蛋白质印迹技术的广泛方法来描述NK 1 R介导的呕吐信号转导，其涉及磷脂酶C的活化和相应的下游信号，包括细胞外Ca 2+流入和细胞内Ca 2+释放在呕吐中的作用，以及Akt/GSK-3αβ通路是否可以调节诱发性呕吐。不仅关于呕吐的细胞内机制的信息很少，而且迫切需要替代的广谱止吐药来保护所有患有由细胞毒性化疗剂引起的呕吐的癌症患者。这项提案的发现不仅将介绍几种新的高效止吐药，而且还可能有助于揭示通用止吐药的潜力，这将降低预防癌症，艾滋病毒或胃肠道疾病患者社区恶心和呕吐的成本。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of PI3K/Akt/GSK-3 Pathway in Emesis and Potential New Antiemetics.

DOI：
10.33696/signaling.1.024
发表时间：
2020-12
期刊：
Journal of cellular signaling
影响因子：
0
作者：
Zhong W;Darmani NA
通讯作者：
Darmani NA

Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function.

DOI：
10.1016/j.phrs.2020.105124
发表时间：
2020-11
期刊：
Pharmacological research
影响因子：
9.3
作者：
Belkacemi L;Darmani NA
通讯作者：
Darmani NA

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).

DOI：
10.3389/fphar.2021.647021
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Zhong W;Darmani NA
通讯作者：
Darmani NA

Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).

DOI：
10.1113/jp282153
发表时间：
2022-02
期刊：
JOURNAL OF PHYSIOLOGY-LONDON
影响因子：
5.5
作者：
Chung, Dillon J.;Madison, Grey P.;Aponte, Angel M.;Singh, Komudi;Li, Yuesheng;Pirooznia, Mehdi;Bleck, Christopher K. E.;Darmani, Nissar A.;Balaban, Robert S.
通讯作者：
Balaban, Robert S.

Central and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis.