GLOMERULAR LAMININS: STRUCTURE AND FUNCTION

描述（改编自研究者摘要）：层粘连蛋白（LM）是一种大的 异源三聚体细胞外基质糖蛋白在 细胞粘附、增殖、迁移、收缩和分化。每个 肾小球细胞类型表达LM同种型的独特子集。时间 其表达的开关与细胞生长过程中的形态转变相关， 肾小球发生。在一些情况下，细胞分化或分化的起始是细胞周期的一部分。 细胞表型的维持与特定的LM同种型有关。 肾小球系膜细胞（MC）表达LM-8（a1 B1 g1），其结合巢蛋白， 交联到纤维状细胞外基质中并促进附着 和传播。MC还表达LM-9（a1 B1 g1），其仍然定位于 细胞表面上的离散区域，并启动丝状伪足的形成。这 该提案将进一步表征LM亚型指导MC的机制， 功能在第一个具体目标中，我们提出LMa 4链形成了一个 与细丝蛋白-1（肌动蛋白结合蛋白280）的复合物，其功能是产生 力和机械保护的MC在收缩。因为这个综合体是 与血管平滑肌细胞和肠平滑肌共享，我们 我认为它相当于平滑肌 骨骼肌所需的LMa 2-肌营养不良蛋白聚糖-肌营养不良蛋白复合物 收缩性MC表达的两种LM亚型在B的使用上不同 因此，它们也可能与MC表面上的蛋白质结合， 传达了额外的功能特异性。拟议的实验将确定 这些复合物中的分子伴侣。第二个具体目标的目标 确定介导MC收缩的LM受体复合物， 迁移在对各种刺激的生物反应中，蛋白酶被 释放出特定的LM片段在某些情况下， 获得新的生物活性。初步数据显示登月舱的碎片 B1链转移到细胞核，在那里它调节基因表达。它 是第三个具体目标的目标，以确认这些观察结果， 阐明LMB 1在细胞核中发挥作用的机制。进行性肾小球 例如老年性肾小球硬化和糖尿病肾病的疾病， 其特征在于LM同种型表达的变化。进一步阐明 LM亚型调节MC收缩能力的机制， 保护毛细血管壁免于过度扩张，在伤口愈合期间迁移， 维持正常的细胞表型和功能， 疾病发病机理的见解。

DESCRIPTION (Adapted from Investigator's Abstract): Laminin (LM) is a large heterotrimeric extracellular matrix glycoprotein that plays important roles in cell adhesion, proliferation, migration, contraction, and differentiation. Each glomerular cell type expresses a unique subset of LM isoforms. Temporal switches in their expression correlate with morphologic transitions during glomerulogenesis. In some cases, initiation of cellular differentiation or maintenance of cellular pheontype has been linked to a particular LM isoform. Glomerular mesangial cells (MC) express LM-8 (a1B1g1), which binds entactin, cross-links into the fibrillar extracellular matrix and facilitates attachment and spreading. MC also express LM-9 (a1B1g1), which remains localized to discrete regions on the cell surface and initiates filopodia formation. This proposal will further characterize the mechanisms whereby LM isoforms direct MC function. In the first specific aim, we propose that the LMa4 chain forms a complex with filamin-1 (actin binding protein 280) that functions to generate force and mechano-protection of MC during contraction. Because this complex is shared with vascular smooth muscle cells and smooth muscle in the intestine, we propose that it is the smooth muscle equivalent of the LMa2-dystroglycan-dystrophin complex that is required for skeletal muscle contractility. The two LM isoforms expressed by MC differ in their use of B chains; thus it is likely that they also engage proteins on the MC surface that convey additional specificity of function. Proposed experiments will identify the molecular partners in these complexes. The goal of the second specific aim is to define the LM-receptors complexes that mediate MC contraction and migration. During biologic responses to a variety of stimuli, proteases are released that generate specific fragments of LM. In some cases these fragments acquire new biologic activity. Preliminary data show that a fragment of the LM B1 chain is translocated to the nucleus where it regulates gene expression. It is the goal of the third specific aim to confirm these observations and elucidate mechanisms whereby LMB1 acts in the nucleus. Progressive glomerular diseases such as glomerulosclerosis of aging and diabetic nephropathy are characterized by changes in the expression of LM isoforms. Further elucidation of the mechanisms whereby LM isoforms modulate the MC capacity to contract, protect the capillary wall from over distention, migrate during wound healing, and maintain normal cellular phentype and function should provide important insights into disease pathogenesis.