Regulation of BMP signaling in kidney

肾脏 BMP 信号传导的调节

• 批准号: 8146985
• 负责人: HERBERT Y LIN
• 金额: $ 36.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146985
• 关键词: Adult; Amino Acids; Apoptosis; Architecture; BMP2 gene; BMP4; BMP7 gene; Binding; Biochemical; Biological Assay; Bone Morphogenetic Proteins; Cell Culture Techniques; Cell Polarity; Cell Proliferation; Cells; Co-Immunoprecipitations; Communication; Complex; Data; Defect; Embryo; Ensure; Epithelial Cells; Epithelium; Family member; Funding; GDNF gene; Genes; Growth; Heterozygote; Human; Hypertension; In Vitro; Individual; Kidney; Kidney Failure; Knock-out; Ligand Binding; Ligands; MAPK14 gene; Mesenchymal; Mesenchyme; Metanephric Diverticulum; Metanephric structure; Molecular; Morphogenesis; Mus; Mutation; Names; Play; Process; Proteins; Regulation; Renal function; Role; Signal Transduction; Signaling Molecule; Tight Junctions; Transfection; Tubular formation; Wild Type Mouse; bone; bone morphogenetic protein receptor type II; kidney epithelial cell; nephrogenesis; overexpression; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Normal kidney development is essential to ensure proper function of the mature kidney. A crucial step in mammalian kidney development is the regulation of ureteric bud (UB) branching morphogenesis. Bone morphogenetic proteins (BMPs) are important signaling molecules required for kidney development, but the precise functions of individual BMP ligands remain poorly understood (Cain 2008; Blank 2008). Kidneys of BMP4 null heterozygote mice showed slower growth and branching of ureteric buds (Miyazaki 2000, Hartwig 2005). In humans, mutations in the BMP4 gene are associated with anomalous kidney development (Weber 2008). BMP4 normally utilizes BMPRII and not ActRIIA for signaling. BMP4 is expressed in the mesenchyme adjacent to the bodies of ureteric branches, but not in the ureteric bud itself. Surprisingly, ActRIIA, and not BMPRII, is the predominant BMP type II receptor found in the bodies of ureteric branches, thus providing a puzzle as to how BMP4 from the mesenchyme can efficiently signal in UB cells. In the prior funding period, we discovered a GPI-anchored protein named Dragon, and showed that it functions as a BMP co-receptor (Samad 2005) and is widely expressed in tubular epithelial cells of the adult kidney (Xia et al JASN 2010). Importantly, we showed that the presence of Dragon allows BMP4 to gain the ability to signal via ActRIIA. Here, we present preliminary data that Dragon is highly expressed in epithelial cells of ureteric branches in the embryonic kidney, and that Dragon null embryonic kidneys at E13.5 showed significant decreases in ureteric branching compared to wild-type kidneys. We hypothesize that Dragon plays an important role in the communication between mesenchymal and ureteric epithelial cells by facilitating mesenchymal BMP4 signaling through ActRIIA in ureteric bud epithelial cells. The biochemical mechanisms of action of Dragon in BMP4 signaling will be studied in Specific Aim I. The role of Dragon during kidney development will be determined by analyzing Dragon null embryonic metanephros in Specific Aim II. Completion of the proposed studies will enhance our understanding of the regulation of BMP signaling, and provide clues to their crucial roles during kidney development. PUBLIC HEALTH RELEVANCE: Reductions in branching morphogenesis and nephrogenesis (renal hypodysplasia) result in abnormal renal architecture and in renal failure and adult-onset hypertension. The cellular and molecular processes involved are poorly understood, but abundant evidence suggests that bone morphogenetic (BMP) signaling is critically involved. We will study the role of the BMP co-receptor Dragon in BMP signaling in kidney development and function.

描述（由申请人提供）：正常的肾脏发育对于确保成熟肾脏的正常功能至关重要。哺乳动物肾脏发育的关键步骤是输尿管芽（UB）分支形态发生的调节。骨形态发生蛋白（BMP）是肾脏发育所需的重要信号分子，但是单个BMP配体的精确功能仍然很少了解（Cain 2008; Blank 2008）。 BMP4无效杂合子小鼠的肾脏显示出输尿管芽的生长较慢和分支（Miyazaki 2000，Hartwig 2005）。在人类中，BMP4基因中的突变与异常的肾脏发育有关（Weber 2008）。 BMP4通常利用BMPRII，而不是Actriia进行信号传导。 BMP4在与输尿管分支的身体相邻的间充质中表达，但在输尿管芽本身中不表示。令人惊讶的是，Actriia，而不是BMPRII是在输尿管分支体内发现的主要BMP II型受体，因此提供了一个难题，即从间质中的BMP4如何有效地在UB细胞中信号。在以前的资金期间，我们发现了一种名为Dragon的GPI锚定蛋白，并表明它是BMP共受体的（Samad 2005），并在成年肾脏的管状上皮细胞中广泛表达（Xia等人Jasn 2010）。重要的是，我们表明龙的存在允许BMP4获得通过Actriia发出信号的能力。在这里，我们提供了初步数据，表明龙在胚胎肾脏的输尿管分支的上皮细胞中高度表达，而在E13.5处的Dragon Null Null胚胎肾脏在输尿管分支中与野生型肾脏相比显示出显着降低。我们假设龙通过在输尿管芽上皮细胞中通过actriia促进间质BMP4信号传导，在间质和输尿管上皮细胞之间的通信中起着重要作用。在特定的目标I中将研究龙在BMP4信号中的生化机制。龙在肾脏发育中的作用将通过分析特定目标II中的龙Null Null Null Embryonic Metanephros来确定。拟议研究的完成将增强我们对BMP信号调节的理解，并为其在肾脏发育过程中的关键作用提供线索。 公共卫生相关性：分支形态发生和肾脏发生的减少（肾功能下降）会导致肾脏异常，肾功能衰竭以及成人发作的高血压。所涉及的细胞和分子过程知之甚少，但是大量证据表明，骨形态发生（BMP）信号密切涉及。我们将研究BMP共受体龙在BMP信号传导中的作用在肾脏发育和功能中。