Unraveling Neural Circuitry in Peripheral Cancer Pathogenesis: From Local Innervation to Systemic Influences
揭示周围癌症发病机制中的神经回路:从局部神经支配到全身影响
基本信息
- 批准号:10687571
- 负责人:
- 金额:$ 153.52万
- 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:2023-09-26 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectBrainCancer BiologyCellsCentral Nervous SystemComplexCranial NervesDevelopmentDiseaseEpigenetic ProcessGeneticGliomaGoalsGrowthHomeostasisLogicLungMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMapsMembraneModelingMolecularNatural regenerationNeoplasm MetastasisNerveNervous SystemNervous System controlNeuronsNeurosciencesPathogenesisPeripheralPeripheral Nervous SystemPeripheral Nervous System NeoplasmsProcessPropertyRoleSecond Primary CancersSignal TransductionSiteSynapsesSystemTissuesbioelectricitycancer cellcancer sitecell typeinnovationlensneoplastic cellnerve stem cellnerve supplyneuralneural circuitneural networkneurotransmissionnew therapeutic targetparacrinesmall cell lung carcinomatooltumortumor initiationtumor microenvironmenttumor progressiontumorigenesis
项目摘要
Project Summary
The complex processes orchestrating cancer pathogenesis remain incompletely understood. Though most
studies have focused on understanding the genetic and epigenetic abnormalities leading to malignant
transformation, it is now well understood that cancers additionally integrate various inputs from their
microenvironment to instruct their growth. From homeostasis to regeneration, the nervous system is responsible
for the maintenance of each tissue and cell. It is therefore no surprise that neural activity is emerging as a critical
regulator of cancer growth. We have recently shown that neuronal activity in the brain heavily influences brain
cancer both through paracrine mechanisms, and more importantly through direct functional electrochemical
integration of malignant cells into neural circuitry via bona fide neuron-glioma synapses. These studies highlight
an underappreciated aspect of cancer biology that emphasize the electrical component of cancers of the brain.
The idea that glioma cells, derived from various neural precursor cells, have the ability and machinery to co-opt
neural signals, though astonishing, does extend the logic that they possess functional remnants of the cell types
from which they emerge. Yet, whether non-glial derived neoplastic cell types possess the ability to similarly
interact with neural networks and if the bioelectric state of the microenvironment similarly drives tumor
pathogenesis in the periphery remains to be elucidated. The goal of this proposal is to map and evaluate
peripheral tumor innervation by understanding the reciprocal interactions between cancers, the local peripheral
nervous system, and the systemic interactions with the central nervous system (the brain). As there is much to
unravel while navigating peripheral tumor innervation, we will use small cell lung cancer (SCLC) as a model to
investigate how peripheral tumors functionally integrate into neural networks. This proposal seeks to understand
how local and systemic interactions between the peripheral and central nervous systems control and alter the
bioelectric state of the primary and secondary sites of cancer growth to influence tumor initiation, development,
and metastasis. Using innovative classic and systems neuroscience tools, we will map the dynamic neural circuits
involved in SCLC tumor innervation, interrogate how vagal nerve activity (the main cranial nerve of the
peripheral nervous system) directly affects tumor pathogenesis at the cellular and molecular level, assess how
the lung as a whole is bioelectrically altered over the course of tumorigenesis, and understand if systemic
dynamics between the central nervous system, the peripheral nervous system, and the tumor are coordinated in
their activity to fuel cancer growth. We will thus extend this bioelectric property of cancer biology to a new set of
malignancies viewed through a holistic lens - from the molecular to the tissue level, from local to systemic
innervation, and from initiation to metastasis; this perspective of electric dysregulation may prove
transformative for these intractable diseases by identifying novel therapeutic targets that normalize the tumor
microenvironment and answer fundamental questions in this emerging field of cancer neuroscience.
项目摘要
协调癌症发病机制的复杂过程仍然不完全清楚。尽管大多数
研究的重点是了解导致恶性的遗传和表观遗传异常。
转变,现在已经很好地理解了癌症额外地整合了来自其
微环境来指导它们的成长。从动态平衡到再生,神经系统负责
用来维持每个组织和细胞。因此,神经活动正在成为一种关键的
癌症生长的调节器。我们最近的研究表明,大脑中的神经元活动严重影响大脑。
癌症既通过旁分泌机制,更重要的是通过直接功能电化学
通过真正的神经元-胶质瘤突触将恶性细胞整合到神经回路中。这些研究强调了
癌症生物学中未被重视的一个方面,强调脑癌的电子成分。
从各种神经前体细胞衍生而来的胶质瘤细胞有能力和机制增选
神经信号虽然令人惊讶,但确实扩展了它们拥有细胞类型的功能残留物的逻辑
他们从那里走出来。然而,非神经胶质来源的肿瘤细胞类型是否具有类似的能力
与神经网络相互作用以及微环境的生物电状态是否类似地驱动肿瘤
外周发病机制尚不清楚。这项提案的目标是绘制和评估
通过了解肿瘤与局部周围肿瘤之间的相互作用来支配周围肿瘤
神经系统,以及与中枢神经系统(大脑)的系统相互作用。因为有很多事情要做
在导航肿瘤周围神经支配的同时,我们将以小细胞肺癌(SCLC)为模型
研究外周肿瘤如何在功能上整合到神经网络中。这项提议试图理解
外周和中枢神经系统之间的局部和全身相互作用如何控制和改变
肿瘤生长的初级和次级部位的生物电状态影响肿瘤的发生、发展
和转移。使用创新的经典和系统神经科学工具,我们将绘制动态神经回路
参与小细胞肺癌肿瘤的神经支配,盘问迷走神经是如何活动的(主要的脑神经
外周神经系统)在细胞和分子水平上直接影响肿瘤的发病机制,评估
肺作为一个整体在肿瘤发生的过程中会发生生物电学变化,并了解系统性
中枢神经系统、周围神经系统和肿瘤之间的动力学是协调的
它们的活动助长了癌症的生长。因此,我们将把癌症生物学的这种生物电学特性扩展到一组新的
从分子到组织水平,从局部到全身的整体视角看待恶性肿瘤
神经支配,以及从起始到转移;这种电失调的观点可能证明
通过确定使肿瘤正常化的新治疗靶点,对这些顽固性疾病具有变革性
并回答这一新兴癌症神经科学领域的基本问题。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Humsa Venkatesh其他文献
Humsa Venkatesh的其他文献
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{{ truncateString('Humsa Venkatesh', 18)}}的其他基金
Microenvironment-driven electrical regulation of primary and secondary brain tumor progression
原发性和继发性脑肿瘤进展的微环境驱动的电调节
- 批准号:
10039557 - 财政年份:2020
- 资助金额:
$ 153.52万 - 项目类别:
Microenvironment-driven electrical regulation of primary and secondary brain tumor progression
原发性和继发性脑肿瘤进展的微环境驱动的电调节
- 批准号:
10540819 - 财政年份:2020
- 资助金额:
$ 153.52万 - 项目类别:
Microenvironment-driven electrical regulation of primary and secondary brain tumor progression
原发性和继发性脑肿瘤进展的微环境驱动的电调节
- 批准号:
10523145 - 财政年份:2020
- 资助金额:
$ 153.52万 - 项目类别:
A Mechanistic Understanding of Neuronal Activity Promotion of High-Grade Glioma Growth through Activity-Regulated Secretion of Neuroligin-3
通过活性调节的 Neuroligin-3 分泌促进高级别胶质瘤生长的神经元活性的机制理解
- 批准号:
9333286 - 财政年份:2015
- 资助金额:
$ 153.52万 - 项目类别:
A Mechanistic Understanding of Neuronal Activity Promotion of High-Grade Glioma Growth through Activity-Regulated Secretion of Neuroligin-3
通过活性调节的 Neuroligin-3 分泌促进高级别胶质瘤生长的神经元活性的机制理解
- 批准号:
8982147 - 财政年份:2015
- 资助金额:
$ 153.52万 - 项目类别:
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