纤维化IV型胶原蛋白沉积在果蝇脂肪体中的正常和病理学作用

基膜是胞外间质（ECM）蛋白的平面复合物。它和它的主要组分IV型胶原蛋白是形态发生、细胞信号传导、创面愈合、免疫应答、和肿瘤进展的重要调控因子。基膜组分的相互作用如何决定基膜组装成均匀的薄片，而不是无规则的聚集体，或这些组分是否有其他组装模式目前未知。ECM的组装或组成缺陷导致多种疾病，如基膜和其他ECM成分过多及异常累积引起的纤维化疾病。但是，人们对引发累积的损伤反应机制知之甚少。我拟研究IV型胶原蛋白基膜外沉积物在正常和病理条件下对组织发育的作用。我计划（1）研究IV型胶原蛋白基膜外沉积物在脂肪体中的作用，而这种沉积代表了一种新的ECM整合方式，（2）阐明天然免疫系统对ECM聚集物的反应或抑制反应机制（3）用正常以及病理纤维化聚集体作为模型测试多种胶原蛋白结合蛋白的体内抗纤维化潜能。本课题将揭示ECM整合新方式，推进理解脂肪体细胞整合成脂肪体方式及医疗相关的ECM免疫系统相互作用.

Basement membranes (BMs) are planar complexes of extracellular matrix (ECM) proteins underlying epithelial and endothelial tissues and surrounding muscles, nerves and adipocytes. BMs and their main component Collagen IV are important regulators of morphogenesis, cell signaling, wound healing, immune responses and tumor progression. Multiple interactions among BM components have been described in vitro. However, it is not known how these interactions determine the assembly of BMs into homogeneously thin sheets rather than amorphous aggregates or whether alternative modes of organization for these ECM components are possible. Besides their roles in normal developmental and physiology, a wide array of human disorders result from defects in ECM assembly or composition. Such is the case of fibrotic diseases, characterized by excessive and aberrant accumulation of BM and other ECM material triggered by damage reaction mechanisms poorly understood. The techniques available in Drosophila, coupled to conservation of BM components and little genetic redundancy, offer many advantages and opportunities to understand fibrotic aggregates and gain insights into the roles of BM components in normal and altered physiology. Taking advantage of our expertise, preliminary data and Drosophila genetic tools, I propose to study the normal and pathological roles of Collagen IV non-BM deposits. I hypothesize that non-BM Collagen IV deposits have important biological effects in both normal tissue development and pathological conditions. To test this main hypothesis, the research I propose here intends to (1) characterize the normal role of Collagen IV non-BM deposits in adipose tissue, which represent a novel form of ECM organization, (2) elucidate mechanisms by which the innate immune system reacts or suppresses reactions to ECM aggregates and (3) use both normal and pathological fibrotic aggregates as a model to test the antifibrotic potential in vivo of several Collagen-binding proteins. By demonstrating the functional importance of non-BM Collagen IV, the research I propose will uncover novel ways of ECM organization. It will also fill a long-standing gap in the understanding of the organization into tissues of adipose cells, which form true tissues despite being non-epithelial. Research proposed here will also uncover clinically-relevant ECM-immune system interactions. Finally, results from this project may have broad implications for the understanding and treatment of fibrotic diseases and other diseases involving abnormal ECM accumulation.