WNK KINASES IN DEVELOPMENT

WNK 激酶正在开发中

• 批准号: 9269593
• 负责人: ANDREAS JENNY
• 金额: $ 38.41万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269593
• 关键词: Address; Adult; Affect; Area; Binding; Biological Assay; Biological Models; Cancer cell line; Cardiovascular system; Cations; Cell Volumes; Cells; Chlorides; Clinical; Complex; Data; Defect; Development; Developmental Process; Dose; Drosophila genus; Embryo; Eye; Generations; Genetic; Genetic Epistasis; Heart; Heart Atrium; Heart Diseases; Hereditary Sensory Neuropathy; Homologous Gene; Human; Hypertension; In Vitro; Invertebrates; Ion Transport; Ions; Kidney; Lead; Leg; Ligands; Light; Lysine; Malignant Neoplasms; Mediating; Methods; Molecular; Mus; Mutation; Nervous system structure; Organogenesis; Orthologous Gene; Pattern; Phenotype; Phosphorylation; Phosphotransferases; Protein Kinase; RNA Interference; Regulation; Research; Role; Signal Pathway; Stem cells; Syndrome; Tertiary Protein Structure; Testing; Time; Type II Pseudohypoaldosteronism; Ventricular; WNT Signaling Pathway; Wing; Wit; Work; Zebrafish; angiogenesis; autonomic neuropathy; base; beta catenin; cell type; defined contribution; experimental study; fly; gain of function; hyperkalemia; in vivo; knock-down; mutant; neurodevelopment; novel; public health relevance; pulmonary arterial hypertension; receptor; relating to nervous system; symporter; tissue culture; tool

 DESCRIPTION (provided by applicant): Mutations in WNK1/4 (With No Lysine [K] kinases) cause autosomal dominant Gordon's syndrome (a.k.a. Pseudohypoaldosteronism Type II) characterized by hypertension, hyperkalemia, and reflecting the fact that WNK kinases are critical regulators of Na+/K+/Cl- co-transporters (CCCs) controlling cell volume and ion reabsorption in the kidney. Recently has it become clear that Wnk kinases also have important functions during development: WNK1 deficiency causes angiogenesis defects and hypoplastic atrial and ventricular heart chambers in mice and neural defects causing Hereditary Sensory and Autonomic Neuropathy type II (HSANII) in humans. At least some functions of Wnk kinases are conserved, as recent evidence suggests that Wnks have a function in neural development in mice, zebrafish, and Drosophila. We identified the single fly ortholog of Wnks as a regulator of canonical Wnt signaling, an unexpected and novel function of Wnks that appears to be similar in human cells. The canonical Wnt/β-Catenin signaling pathway is highly conserved from invertebrates to humans and has a broad and essential role in regulating proliferation of different cell types including stem cells. Interestingly, hyperactivation of Wnt signaling can lead to pulmonary arterial hypertension. Furthermore, the proliferation of certain cancer cell lines wit high β-Catenin activity is dependent on WNK1, suggesting an intricate connection between Wnks and Wnt signaling. The role of Wnk kinases during development was previously unrecognized; therefore, how Wnk functions in this context is not understood. We will thus elucidate the functions of Wnk during development, determine the extent to which they are mediated by Wnt signaling, and identify novel Wnk effectors essential for these functions. Our research strategy will shed much needed light on how Wnk affects organogenesis and thus will likely have implications for human heart disease and cancer.

 描述（由申请人提供）：WNK 1/4（无赖氨酸[K]激酶）突变导致常染色体显性戈登综合征（又名戈登综合征）。假性醛固酮减少症II型），以高血压、高钾血症为特征，反映了WNK激酶是Na+/K+/Cl-共转运蛋白（CCC）的关键调节剂，控制肾脏中的细胞体积和离子重吸收。最近已经清楚Wnk激酶在发育过程中也具有重要功能：WNK 1缺乏导致小鼠中血管生成缺陷和发育不良的心房和心室心腔，以及导致人类遗传性感觉和自主神经病II型（HSANII）的神经缺陷。Wnk激酶的至少一些功能是保守的，因为最近的证据表明Wnk在小鼠、斑马鱼和果蝇的神经发育中具有功能。 我们鉴定了Wnks的单蝇直系同源物作为经典Wnt信号传导的调节剂，这是Wnks的一种意想不到的新功能，在人类细胞中似乎是相似的。经典的Wnt/β-连环蛋白信号通路从无脊椎动物到人类都是高度保守的，并且在调节包括干细胞在内的不同细胞类型的增殖中具有广泛和重要的作用。有趣的是，Wnt信号的过度激活可以导致 肺动脉高压此外，具有高β-连环蛋白活性的某些癌细胞系的增殖依赖于WNK 1，表明Wnks和Wnt信号传导之间存在复杂的联系。 Wnk激酶在发育过程中的作用以前未被认识;因此，Wnk在这种情况下如何发挥作用尚不清楚。因此，我们将阐明Wnk在发育过程中的功能，确定它们在多大程度上是由Wnt信号介导的，并确定新的Wnk效应器对这些功能至关重要。我们的研究策略将揭示Wnk如何影响器官发生，从而可能对人类心脏病和癌症产生影响。