Biomechanical drivers of cystogenesis

项目总结 小管的特征是被极化的上皮细胞包围的管腔空间。细胞 极化，即极性因素沿垂直轴的不对称分离 至黏附底物(根尖基底极性)或平行于上皮片(平面细胞 极性)是细胞功能和反应的方向性所必需的，例如吸收 以及分泌、细胞运动和增殖。心尖-基底极性的维持依赖于 细胞-细胞和细胞-细胞外力生物信号的整合 矩阵(ECM)交互。这些协同交易的脱轨导致了肾小管 诸如肾小管扩张或囊变，以及生理性肾小管丢失等畸形 功能，这是多囊肾病的病因学。然而，到目前为止，有 没有实验或计算研究来描述生物力学失衡 可能有助于囊性病变的发生。越来越多的证据表明，PKD1的突变 常染色体显性遗传性多囊肾病致病基因与 上皮细胞的核心机械敏感机制异常。我们的预赛 结果表明，PKD1或睫状肌Ift88基因缺失引起的囊变 通过消融主要的ECM受体整合素-1，可以恢复到正常的表型。 基于这些观察，我们假设生物机械力的平衡 在细胞间连接和细胞外基质之间产生的信号是建立和维持肾小管的关键 正直。为了验证这一假设，我们将使用高度整合的理论和实验 分析，包括生物物理、细胞生物学、计算和活体方法。我们的 方法可以导致识别可以逆转这种情况的新的药物靶点 从根本上说是独一无二的生物物理疾病机制。拟议的研究将建立一个 肾脏囊变的生物物理机制的综合模型，它们可能 发现可以作为治疗靶点的新的效应器通路。

PROJECT SUMMARY Tubules are characterized by a luminal space surrounded by polarized epithelial cells. Cell polarization, that is the asymmetric segregation of polarity factors along the axis perpendicular to the adhesion substrate (apicobasal polarity) or parallel to the epithelial sheet (planar cell polarity), is required for the directionality of cellular functions and responses, such as absorption and secretion, cell movement, and proliferation. The maintenance of apical-basal polarity relies on the integration of mechanobiological signals deriving from cell-cell and cell-extracellular matrix (ECM) interactions. Derailment of these concerted exchanges leads to tubular malformations such as tubular dilation, or cystogenesis, and loss of tubule physiological function, which are pathognomonic of polycystic kidney disease. However, to date, there has been no experimental or computational studies that describe how biomechanical imbalance could contribute to cystogenesis. Increasing evidence suggests that mutations in the Pkd1 gene, causative of autosomal dominant polycystic kidney disease, are associated with abnormalities in the core mechanosensitive machinery of epithelial cells. Our preliminary findings indicate that the cystogenesis caused by the deletion of Pkd1 or the ciliary Ift88 gene can be reverted to the normal phenotype by the ablation of integrin-?1, a main ECM receptor. Based on these observations, we hypothesize that the equilibrium of the biomechanical forces generated between intercellular junctions and ECM is essential to establish and maintain tubular integrity. To test this hypothesis, we will use highly integrated theoretical and experimental assays, including biophysical, cell biological, computational, and in vivo approaches. Our approach can lead to the identification of novel drug targets that could reverse this fundamentally unique biophysical disease mechanism. The proposed studies will establish a comprehensive model of the biophysical mechanisms of renal cystogenesis, and they may uncover new effector pathways that could be therapeutically targeted.