Bcl-2 & Branching Morphogenesis

Bcl-2

• 批准号: 7373597
• 负责人: CHRISTINE M SORENSON
• 金额: $ 26.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373597
• 关键词: Adhesives; Affect; Apoptosis; Appendix; BH4 Domain; Binding; Cell Adhesion; Cell Death; Cell Survival; Cells; Child; Collagen; Condition; Data; Development; Dysplasia; Embryo; Exhibits; Family member; Focal Adhesion Kinase 1; Gel; In Vitro; Incubated; Kidney; Maintenance; Mediating; Mesenchymal; Mesenchyme; Metanephric Diverticulum; Metanephric structure; Morbidity - disease rate; Morphogenesis; Mus; Organ Culture Techniques; Organism; Pathogenesis; Peptides; Phenotype; Physiological; Play; Proteins; Risk; Role; Spinal Cord; Stimulus; Tyrosine; blastema; in vivo; insight; mortality; nephrogenesis; paxillin; precursor cell; tetrahydrobiopterin

DESCRIPTION (provided by applicant): Bcl-2 protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Mice deficient in bcl-2 (bcl-2 -/-) develop renal hypoplastic/cystic dysplasia, a condition that leads to significant morbidity and mortality in children. The precise mechanism of action of bcl-2 has not been elucidated. Our hypothesis is that early embryonic expression of bcl-2 facilitates morphogenesis by supporting survival of precursor cells allowing them to be less adherent and migratory without the threat of apoptosis. Bcl-2 may facilitate survival of precursor cells and/or play a more "active" role during morphogenesis by interacting with other proteins such as paxillin. Our data demonstrate that paxillin interacts with the bcl-2 BH4 domain in embryonic kidneys. The bcl-2 BH4 domain is sufficient and necessary for its cell survival activity. Bcl-2 with the BH4 domain deleted lacks the survival function but still avidly binds to other bcl-2 family members. We will determine the domain(s) of paxillin that interact with bcl-2 and their influence on cell adhesive mechanisms during kidney development. Our preliminary data indicate that ureteric bud (UB) branching morphogenesis is adversely affected in bcl-2 -/- mice. Metanephroi from bcl-2 -/- mice undergo decreased UB branching in organ culture and bcl-2 -/- UB cells fail to undergo branching morphogenesis in collagen gels. Furthermore, wild-type embryonic kidneys incubated with bcl-2 BH4 domain peptide exhibit defective UB branching morphogenesis. We will investigate the role bcl-2 plays during UB branching and whether aberrant UB branching contributes to excessive apoptosis of the metanephric blastema in bcl-2 -/- mice. We will determine whether the abnormalities of renal development in bcl-2 -/- mice is primarily or exclusively the result of the absence of bcl-2 in the UB or metanephric mesenchyme. Therefore, understanding the normal functions of bcl-2 during nephrogenesis and the consequences of its interaction with paxillin will give us important insight into kidney morphogenesis and pathogenesis.

描述（由申请人提供）：BCL-2可保护细胞免受各种刺激引发的细胞凋亡，包括失去细胞粘附。缺乏Bcl-2（Bcl-2 - / - ）的小鼠会出现肾功能低下/囊性发育不良，这种疾病会导致儿童的发病率显着和死亡率。 Bcl-2的确切作用机理尚未阐明。我们的假设是，Bcl-2的早期胚胎表达通过支持前体细胞的存活，从而促进形态发生，从而使它们的依从性和迁移较低，而不会受到凋亡的威胁。 Bcl-2可以通过与其他蛋白质（如帕西林）相互作用来促进前体细胞的存活和/或在形态发生过程中起更加“活跃”的作用。我们的数据表明，帕西林与胚胎肾脏中的Bcl-2 BH4结构域相互作用。 Bcl-2 BH4结构域对于其细胞存活活性就足够且必要。带有BH4域的Bcl-2缺失了生存功能，但仍然与其他BCL-2家族成员保持着平均结合。我们将确定与Bcl-2相互作用的Paxillin的结构域及其对肾脏发育过程中细胞粘合剂机制的影响。我们的初步数据表明，在Bcl-2 - / - 小鼠中，输尿管芽（UB）分支形态发生受到不利影响。来自Bcl-2 - / - 小鼠的Metanephroi在器官培养中经历了UB分支的降低，而Bcl-2 - / - UB细胞在胶原蛋白凝胶中未能进行分支形态发生。此外，与Bcl-2 BH4域肽孵育的野生型胚胎肾脏表现出缺陷的UB分支形态发生。我们将研究Bcl-2在UB分支过程中的作用，以及异常UB分支是否有助于Bcl-2 - / - 小鼠中跨虫胚胎的过度凋亡。我们将确定Bcl-2 - / - 小鼠中肾脏发育的异常是否主要或仅是UB或元eNaphric间质中不存在Bcl-2的结果。因此，了解肾脏发生过程中Bcl-2的正常功能及其与Paxillin相互作用的后果将使我们对肾脏形态发生和发病机理的重要见解。