Mechanisms of death receptor-mediated apoptosis

细胞分裂和程序性细胞死亡之间的平衡对正常发育、维持体内平衡和免疫系统功能至关重要。不适当调节的细胞死亡有助于多种人类疾病的发病机制，包括神经退行性疾病、自身免疫性综合征和几种形式的癌症。死亡受体如Fas和TNFR1是细胞表面传感器，响应特定的细胞外死亡信号，通过凋亡触发细胞破坏。最近的研究表明，通过Fas和TNFR1进行信号转导的机制存在显著差异，但它们都需要接头蛋白FADD来诱导细胞凋亡。在这项研究中，我们将通过生物化学和生物物理学的研究来阐明FADD及其结合伙伴之间相互作用的分子基础。本研究将提高我们对死亡受体诱导的细胞凋亡及其信号机制差异的认识。详细了解死亡受体信号传导的这些方面具有重要意义，因为它们代表了关键的调控步骤，可能对有针对性的干预措施有用。

The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death signals. Recent studies have demonstrated that the mechanisms of signal transduction through Fas and TNFR1 differ significantly, however, they both require the adaptor protein FADD to induce apoptosis. In this study we will elucidate the molecular basis of the interactions between FADD and its binding partners using biochemical and biophysical studies. This research will improve our understanding of death receptor-induced apoptosis and the differences in signalling mechanisms. A detailed knowledge of these aspects of death receptor signalling is of significance because they represent critical regulatory steps that could be useful for targeted interventions.