Regulation of Peripheral Proteostasis

项目摘要 这个建议是为了检查的基础上组织间的信号调节生物体蛋白质。我们 组织健康受到外周组织和神经元之间信号的影响， 多细胞动物中的整合蛋白稳态网络（PN）。这确保了每个组织表达的蛋白质组 与其相应的组织PN接合以平衡合成、折叠和功能以及降解。在 除了协调每个组织内的蛋白质组健康外，组织间信号传导还影响生物体 对衰老过程中蛋白毒性的反应。我们之前的工作提供了一些关键的观察结果， 外周蛋白质稳态在C.优雅我们发现，生物热休克反应（HSR）是 由一种特殊的感觉神经元调节，该神经元通过血清素将细胞应激信号传递给躯体神经元。 任何单个组织内蛋白质稳态的不平衡都会向外周组织发出应激反应信号。 接受组织导致补偿性跨细胞伴侣反应，并且生殖系干细胞 在生殖成熟时，利用整体染色质抑制调节外周体细胞组织中的HSR 在老化过程中启动PN故障的信号。这些研究为这一提案提供了基础， 外周蛋白质代谢抑制的调节和特性。我们提出以下目标：（1）建立 在神经元，体壁肌细胞，和肠的组织PN的功能特性的C。elegans，（2）To 识别神经元，体壁肌肉细胞和肠道之间的通信信号通路， 外周蛋白质稳态，以及（3）检查蛋白毒性蛋白Abeta、tau或polyQ如何影响外周 蛋白质代谢抑制，以及老化对聚集和毒性的影响。

PROJECT SUMMARY This proposal is to examine the basis of intertissue signaling in the regulation of organismal proteostasis. We posit that tissue health is influenced by signals between peripheral tissues and neurons to establish an integrated proteostasis network (PN) in metazoans. This ensures that the proteome expressed by each tissue is engaged with its corresponding tissue PN for balanced synthesis, folding and function, and degradation. In addition to coordinating proteome health within each tissue, intertissue signaling affects the organismal response to proteotoxicity during aging. Our previous work provided some of the key observations to suggest a role for peripheral proteostasis in C. elegans. We showed that the organismal heat shock response (HSR) is regulated by a specific sensory neuron that communicates the cell stress signal via serotonin to the somatic tissues, that an imbalance in proteostasis within any single tissue sends a stress response signal to peripheral receiving tissues resulting in a compensatory transcellular chaperone response, and that germ line stem cells regulate the HSR in peripheral somatic tissues at reproductive maturity using a global chromatin repression signal to initiate PN failure in aging. These studies provide the basis for this proposal to understand the regulation and properties of peripheral proteostasis. We propose the following Aims: (1) To establish the functional properties of the tissue PN in neurons, body wall muscle cells, and intestine of C. elegans, (2) To identify the signaling pathways for communication between neurons, body wall muscle cells, and intestine for peripheral proteostasis, and (3) To examine how proteotoxic proteins Abeta, tau or polyQ affects peripheral proteostasis, and the effects of aging on aggregation and toxicity.