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: 8763094
• 负责人: Lino Tessarollo
• 金额: $ 83.41万
• 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/8763094
• 关键词: Accounting; Address; Adult; Affect; Aggressive behavior; Animal Model; Binding; Birth; Blood; Brain-Derived Neurotrophic Factor; Calcium; Calcium Channel; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Line; Cell physiology; Cells; Cytoplasmic Tail; Cytotoxic T-Lymphocytes; Data; Development; Dilated Cardiomyopathy; Enlargement of lymph nodes; Etiology; Goals; Greater sac of peritoneum; Heart; Heart Hypertrophy; Homeostasis; Homologous Gene; Human; Immune; Immune system; Impairment; Inflammatory; Inflammatory Response; Intervention; Left; Leukocyte Trafficking; Leukocytes; Lymphocyte; Lymphoma; Malignant Neoplasms; Mediating; Mus; Mutant Strains Mice; Nephroblastoma; Nervous system structure; Neuroblastoma; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophin 3; Pancreatic carcinoma; Performance; Peritonitis; Phosphotransferases; Population; Prostate carcinoma; Protein Isoforms; Reporting; Role; Scaffolding Protein; Signal Transduction; Stream; Stress; Structure; System; Wild Type Mouse; cell motility; cytokine; in vivo; leukemia virus; lymph nodes; migration; mouse model; neurotrophic factor; outcome forecast; overexpression; receptor; response; sarcoma; trafficking; tumor

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. Interestingly, the cytoplasmic tail of the neurotrophin-3 (NT3) truncated TrkCT1- receptor is highly conserved among species, suggesting the potential for important functions in vivo. We have recently shown that NT3 interaction with TrkCT1 activates Arf6-Rac1 signaling through the scaffold protein Tamalin. We found that TrkCT1 binds also the Tamalin homolog Cybr, a scaffold protein highly expressed in the immune system. NT3 treatment of the EL4 lymphoma cell line that express endogenously both TrkCT1 and Cybr, induces intracellular re-localization of Cybr. Since Cybr is involved in pro-inflammatory cytokine-modulated cell migration, our results suggest that TrkCT1 may modulate the recruitment and migration of specific leukocyte cell populations. Indeed, in mouse in which we have deleted Cybr we find specific deficits in blood circulating leukocytes and lymphocytes present in the lymph nodes. Moreover, in a Th1-polarized-mouse model, lymphocyte trafficking is impaired by loss of Cybr and Cybr-deficient mice with aseptic peritonitis have fewer cells than controls present in the peritoneal cavity and fewer leukocytes leaving the blood stream. Mutant mice injected with Moloney-murine sarcoma/leukemia virus develop significantly larger tumors than wild type mice and have reduced lymph node enlargement suggesting reduced cytotoxic T lymphocytes migration. Taken together, these data support a role for Cybr in leukocyte trafficking, especially in response to pro-inflammatory cytokines in stress conditions. We are now investigating which of these Cybr functions are affected by NT-3/TrkC.T1. In a separate project we have investigated whether TrkB Receptors have other functions outside the nervous system. Surprisingly, we found that these receptors control contraction and long-term homeostasis of the mammalian heart. For example, BDNF increases the cardiac contraction force and calcium release in cardiomyocytes through TrkB.T1 and mice lacking TrkB.T1-/- mice show cardiac hypertrophy, calcium channel alteration, dilated cardiomyopathy and reduced heart performances. Together these data suggest that impairment in BDNF/TrkB.T1 signaling can contribute to the etiology of cardiomyopathies.

缺乏激酶结构域的截短的TRK受体同工型在发育过程中和成年人中都大量表达。但是，它们的功能和信号能力在很大程度上是未知的。有趣的是，神经营养蛋白3（NT3）截短的Trkct1-受体的细胞质尾巴在物种之间高度保守，这表明体内重要功能的潜力。我们最近表明，NT3与TRKCT1的相互作用通过支架蛋白质塔玛蛋白激活ARF6-RAC1信号传导。我们发现TRKCT1还结合了塔玛蛋白同源物Cybr，这是一种在免疫系统中高度表达的支架蛋白。 NT3的EL4淋巴瘤细胞系的NT3治疗均表达TRKCT1和CYBR，诱导Cybr的细胞内重新定位。由于CYBR参与了促炎性细胞因子调节的细胞迁移，我们的结果表明TRKCT1可能会调节特定白细胞细胞群体的募集和迁移。确实，在删除Cybr的小鼠中，我们发现淋巴结中存在的血液循环白细胞和淋巴细胞的特定缺陷。此外，在Th1偏振小鼠模型中，淋巴细胞运输受到无菌腹膜炎的Cybr和Cybr缺陷小鼠的损害，其细胞的细胞少于腹膜腔中存在的对照，而留下血液流的白细胞则较少。注射了莫洛尼丝氨酸肉瘤/白血病病毒的突变小鼠比野生型小鼠的肿瘤明显大得多，并且淋巴结肿大降低，表明细胞毒性T淋巴细胞迁移降低。综上所述，这些数据支持Cybr在白细胞运输中的作用，尤其是在压力条件下促炎性细胞因子的响应。我们现在正在研究哪些CYBR函数受NT-3/TRKC.T1的影响。在一个单独的项目中，我们研究了TRKB受体在神经系统之外是否具有其他功能。令人惊讶的是，我们发现这些受体控制着哺乳动物心脏的收缩和长期稳态。例如，BDNF通过TRKB.T1增加了心肌细胞的心脏收缩力和钙释放，而缺乏TRKB.T1 - / - 小鼠的小鼠表现出心脏肥大，钙通道改变，心肌病的扩张和心脏表现降低。这些数据共同表明，BDNF/TRKB.T1信号传导中的损伤可能有助于心肌病的病因。