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保护细胞免受多种刺激引起的细胞凋亡，包括细胞粘附丧失。缺乏bcl-2 （bcl-2 -/-）的小鼠会发生肾发育不全/囊性发育不良，这种情况会导致儿童的严重发病率和死亡率。bcl-2的确切作用机制尚未阐明。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来促进形态发生，使它们在没有凋亡威胁的情况下较少粘附和迁移。Bcl-2可能促进前体细胞的存活和/或通过与其他蛋白（如paxillin）相互作用在形态发生过程中发挥更“活跃”的作用。我们的数据表明，paxillin在胚胎肾脏中与bcl-2 BH4结构域相互作用。bcl-2的BH4结构域是其细胞存活活性的充分必要条件。删除BH4结构域的Bcl-2缺乏存活功能，但仍热切地与其他Bcl-2家族成员结合。我们将确定paxillin与bcl-2相互作用的结构域及其对肾脏发育过程中细胞粘附机制的影响。我们的初步数据表明，bcl-2 -/-小鼠输尿管芽（UB）分支形态发生受到不利影响。bcl-2 -/-小鼠后肾在器官培养中出现UB分支减少，bcl-2 -/- UB细胞在胶原凝胶中不能发生分支形态发生。此外，用bcl-2 BH4结构域肽孵育的野生型胚胎肾表现出UB分支形态发生缺陷。我们将研究bcl-2在UB分支中的作用，以及异常UB分支是否会导致bcl-2 -/-小鼠后肾囊胚过度凋亡。我们将确定bcl-2 -/-小鼠肾脏发育异常主要还是完全是由于UB或后肾间质中缺乏bcl-2的结果。因此，了解bcl-2在肾脏形成过程中的正常功能及其与paxillin相互作用的后果将为我们了解肾脏形态发生和发病机制提供重要的见解。