STRUCTURAL/FUNCTIONAL STUDIES OF SIGNALING COMPLEXES IN APOPTOSIS & INFLAMMATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本实验室致力于阐明细胞凋亡和炎症过程中的信号转导机制。这些通路对于哺乳动物生物学包括免疫调节和细胞内稳态是至关重要的。这些通路的功能障碍可导致严重的人类疾病，如癌症、自身免疫性疾病和退行性疾病。我们研究的一个主要方面与半胱氨酸蛋白酶的抑制和激活有关，半胱氨酸蛋白酶是执行凋亡的半胱氨酸蛋白酶家族。本研究旨在确定半胱天冬酶激活复合物和半胱天冬酶与天然蛋白质抑制剂或小分子抑制剂复合物的晶体结构。我们研究的另一个方面涉及NF-κ B激活的途径和通过先天免疫诱导炎症反应。我们试图确定泛素连接酶，激酶和其他效应物的复合物的晶体结构。为了充分了解分子机制，我们通过生物化学，生物物理和细胞生物学研究补充了结构研究，其中一些研究与该领域的领导者合作。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our laboratory is interested in elucidating the mechanism of signaling transduction in the pathway of apoptosis and inflammation. These pathways are crucial for mammalian biology including immune regulation and cellular homeostasis. Malfunction of these pathways can lead to serious human diseases such as cancer, autoimmune diseases and degenerative diseases. One major aspect of our studies has to do with the inhibition and activation of caspases, a family of cysteine proteases that execute apoptosis. This study seeks to determine crystal structures of caspase activating complexes and caspases in complex with natural protein inhibitors or small molecule inhibitors. Another aspect of our studies deals with the pathway for NF-kappaB activation and the induction of inflammatory responses through innate immunity. We seek to determine crystal structures of complexes of ubiquitin ligases, kinases and other effectors. To fully understand the molecular mechanisms, we complement the structural studies with biochemical, biophysical and cell biological studies, some of which are in collaboration with leaders in the field.