CELLULAR SIGNALING IN RENAL PATHOPHYSIOLOGY

描述(改编自《调查者摘要》)：最新研究 记录了环-3‘，5’-核苷酸磷酸二酯酶的关键重要性 (PDE)同工酶在cAMP信号通路中调节生物学和 肾细胞的病理生物学。拟议的调查是基于一项 工作假说系膜细胞(MC)对 免疫炎症刺激可以被调节和选择性地抑制在 在体外和体内通过药物治疗干预，目标是 细胞内信号通路及其相互作用。主 调节cAMP和cGMP信号通路的靶点是PDE 同工酶。CAMP信号可以通过与其他人的“负串扰” 信号通路抑制MC的过度增殖，还 MC中活性氧代谢物(ROM)的产生。体外研究 将阐明PDE的异构体、定位和调节的模式 原代培养大鼠肾小球系膜细胞的同工酶，并测定其同工酶 对选择拮抗剂的敏感性。蛋白激酶A(PKA)同工酶 C-AMP途径中的关键环节，将在MC中进行研究，特别是在 与PDE导向的cAMP池和功能性末端反应的关系 MC。此外，还将探讨cGMP信号在MC中的作用。少校 目标是勾勒出坎普-PKA所用的“负面相声” 抑制控制MC的丝裂原激活的信号通路 我们还将阐明cGMP的抗促分裂作用。 发信号。进一步的研究将确定其生化基础。 CAMP-PKA通路通过抑制ROM产生的“负串扰” MC中的NADPH氧化酶。最后，在体内，致病机制和新奇 药物治疗将在系膜病大鼠模型中进行研究 增殖性肾小球肾炎(MSGN)，抗Thy-1.1-GN，其中 MC的病理生物学起主导作用。药物治疗 将主要针对PDE同工酶和PKA同工酶进行干预 检查其预防、阻止或逆转各种MSGN的有效性 严重程度，以及MSGN发展的不同阶段。这些 研究将为新的“信号转导靶向”建立一个范例 应用PDE同工酶拮抗剂和 前瞻，用于治疗其他类型的肾小球肾炎。

DESCRIPTION (Adapted from Investigator's Abstract): Recent studies documented a key importance of cyclic-3', 5' -nucleotide phosphodiesterase (PDE) isozymes in cAMP signaling pathways that regulate biology and pathobiology of renal cells. The proposed investigations are based on a working hypothesis that pathobiologic responses of mesangial cells (MC) to immune-inflammatory stimuli can be modulated and selectively suppressed in vitro and in vivo by pharmacotherapeutic interventions that are targeted to intracellular signaling pathways and their mutual interactions. The main target points for modulation of the cAMP and cGMP signaling pathways are PDE isozymes. The cAMP signaling can via "negative crosstalk" with other signaling pathways suppress excessive proliferation of MC and also generation of reactive oxygen metabolites (ROM) in MC. In vitro studies will elucidate the pattern of isoforms, localization, and regulation of PDE isozymes in rat MC in primary cell culture, and then determine their sensitivity to select antagonists. Isozymes of protein kinase A (PKA), an essential link in c AMP pathway, will be examined in MC, especially in relationship to PDE-directed pools of cAMP and functional end-responses of MC. The role of cGMP signaling in MC will be explored as well. The major goal is the delineation of the "negative crosstalk" by which cAMP-PKA inhibits the mitogen-activated signaling pathways that control MC proliferation; we will also elucidate the antimitogenic effect of cGMP signaling. Further studies will determine the biochemical basis of the "negative crosstalk" by which cAMP-PKA pathway inhibits ROM generation by NADPH oxidase in MC. Finally, in vivo, the pathogenic mechanisms and novel pharmacotherapies will be studied in the rat model of mesangial proliferative glomerulonephritis (MSGN), "anti-Thy-1.1-GN," in which pathobiology of MC plays a dominant role. Pharmacotherapeutic interventions, mainly targeted to PDE isozymes and PKA isozymes, will be examined for their efficacy to prevent, block, or reverse MSGN of various grades of severity, and at different stages of MSGN development. These studies will establish a paradigm for novel "signal transduction-targeted" pharmacotherapies of MSGN with use of PDE isozyme antagonists and, prospectively, for treatment of other types of glomerulonephritis.