Role of Trk Receptors in the Development and Function of Non-neuronal Structures

Trk 受体在非神经元结构发育和功能中的作用

• 批准号: 10926011
• 负责人: Lino Tessarollo
• 金额: $ 92.89万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926011
• 关键词: Address; Adult; Aggressive behavior; Animal Model; Astrocytes; Binding; Biology; Birth; Brain-Derived Neurotrophic Factor; Calcium Signaling; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell physiology; Cells; Development; Glucose; Goals; Heart; Homeostasis; Human; Immune; Immune system; Impairment; Inflammatory Response; Intervention; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Mus; Nephroblastoma; Nervous System; Neuroblastoma; Neurotrophic Tyrosine Kinase Receptor Type 2; Organism; Pancreatic carcinoma; Pathway interactions; Phase; Phosphotransferases; Physiological; Prognosis; Prostate carcinoma; Protein Isoforms; Proteins; Reporting; Role; Signal Induction; Signal Transduction; Structure; Structure of beta Cell of islet; System; autocrine; in vivo; insulin secretion; nerve supply; neurotrophic factor; novel; overexpression; paracrine; pharmacologic; receptor

Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. Recently, we have investigated whether TrkB Receptors have other functions outside the nervous system. We found that a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms. Moreover, we reported by deletion and in vivo tagging of endogenous TrkB.T1 that expression of this TrkB isoform in pancreatic beta-cells increases glucose-induced insulin secretion. Importantly, we showed that this pathway is conserved in humans. Altogether, these studies were key to finally providing strong and definitive physiological functions mediated by TrkB.T1 signaling that are independent of its classic dominant/negative role on TrkB.FL or BDNF sequestering activity. In addition, they pave the way for the next phase aimed at identifying the still uncharacterized molecular pathway/s activated by TrkB.T1. So far, we and others have shown that TrkB.T1 regulates Ca++ signaling in astrocytes, cardiomyocytes and pancreatic beta-cells but it is unclear as to which proteins it binds to induce signaling. This is still one of the major open questions in neurotrophin biology. It is likely that the small TrkB.T1 intracellular domain is unable to form stable interactions with proteins precluding their isolation and identification by mass-spectrometry.

缺乏激酶结构域的截短 Trk 受体亚型在发育过程中和成人中大量表达；然而，它们的功能和信号传递能力在很大程度上尚不清楚。最近，我们研究了TrkB受体是否具有神经系统之外的其他功能。我们发现 BDNF 在调节心脏收缩力方面具有一种意想不到的新作用，不依赖于神经系统的神经支配。该功能由心肌细胞中表达的截短 TrkB.T1 受体介导。这些细胞中 TrkB.T1 的缺失会损害钙信号传导并导致心肌病。 TrkB.T1 被心肌细胞产生的 BDNF 激活，表明存在自分泌/旁分泌循环。这些发现揭示了心脏中由 BDNF 激活的新型信号传导机制，并为这种神经营养素通过不同 TrkB 受体亚型的信号传导在生物体稳态中的整体作用提供了证据。此外，我们通过内源性 TrkB.T1 的缺失和体内标记发现，胰腺 β 细胞中这种 TrkB 亚型的表达会增加葡萄糖诱导的胰岛素分泌。重要的是，我们证明这条途径在人类中是保守的。总而言之，这些研究对于最终提供由 TrkB.T1 信号传导介导的强大而明确的生理功能至关重要，这些功能独立于其对 TrkB.FL 或 BDNF 隔离活性的经典显性/负面作用。此外，他们为下一阶段铺平了道路，该阶段旨在识别 TrkB.T1 激活的尚未表征的分子途径。到目前为止，我们和其他人已经证明 TrkB.T1 调节星形胶质细胞、心肌细胞和胰腺 β 细胞中的 Ca++ 信号传导，但尚不清楚它结合哪些蛋白质来诱导信号传导。这仍然是神经营养蛋白生物学中主要的悬而未决的问题之一。较小的 TrkB.T1 胞内结构域可能无法与蛋白质形成稳定的相互作用，从而妨碍了蛋白质的分离和质谱鉴定。

项目成果

Embryonic stem cell-derived motoneurons provide a highly sensitive cell culture model for botulinum neurotoxin studies, with implications for high-throughput drug discovery.

• DOI: 10.1016/j.scr.2011.01.002
• 发表时间: 2011-05
• 期刊: STEM CELL RESEARCH
• 影响因子: 1.2
• 作者: Kiris, Erkan;Nuss, Jonathan E.;Burnett, James C.;Kota, Krishna P.;Koh, Dawn C.;Wanner, Laura M.;Torres-Melendez, Edna;Gussio, Rick;Tessarollo, Lino;Bavari, Sina
• 通讯作者: Bavari, Sina

Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes.

• DOI: 10.1371/journal.pone.0027034
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Graciotti L;Becker J;Granata AL;Procopio AD;Tessarollo L;Fulgenzi G
• 通讯作者: Fulgenzi G

Regulation of Kit Expression in Early Mouse Embryos and ES Cells.

• DOI: 10.1002/stem.2960
• 发表时间: 2019-03
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Todaro F;Campolo F;Barrios F;Pellegrini M;Di Cesare S;Tessarollo L;Rossi P;Jannini EA;Dolci S
• 通讯作者: Dolci S

RanBPM, a scaffolding protein for gametogenesis.

RanBPM，一种配子发生的支架蛋白。

• DOI: 10.1016/b978-0-12-416024-8.00013-1
• 发表时间: 2013
• 期刊: Current topics in developmental biology
• 作者: Puverel,Sandrine;Tessarollo,Lino
• 通讯作者: Tessarollo,Lino

BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation.

• DOI: 10.1083/jcb.201502100
• 发表时间: 2015-09-14
• 期刊: The Journal of cell biology
• 作者: Fulgenzi G;Tomassoni-Ardori F;Babini L;Becker J;Barrick C;Puverel S;Tessarollo L
• 通讯作者: Tessarollo L