Genetic regulation of autophagic cell death

描述（由申请人提供）：细胞生长、分裂和死亡是组织和动物大小的决定因素，这些基本细胞过程中的缺陷会导致各种人类疾病，包括癌症。生长和细胞死亡之间的机械关系在正常动物发育的背景下定义不清，尽管它们一直是许多研究的焦点。细胞凋亡和自噬性细胞死亡是发生在发育过程中的两种最突出的细胞程序性死亡形态。我们正在研究类固醇激活的自噬程序性细胞死亡的果蝇幼虫唾液腺细胞死亡为模型的发展过程中。类固醇的增加触发了一个基因层次，激活了唾液腺中几乎同步的细胞死亡。这些发育调控的细胞死亡利用凋亡基因，包括半胱天冬酶蛋白酶，但唾液腺也具有细胞死亡的形态-通过自噬细胞死亡。半胱天冬酶的突变仅部分抑制唾液腺细胞死亡，我们最近的研究表明类固醇信号传导、由磷酸肌醇3激酶（PI 3 K）调节的生长和该组织的死亡之间存在重要关系。在此，我们建议：（1）确定发育期间唾液腺生长和自噬细胞死亡之间的关系，（2）确定PI 3 K诱导的生长如何影响垂死唾液腺中的类固醇信号传导和细胞破坏机制，以及（3）鉴定在自噬细胞死亡中起作用的新基因。最近的自噬细胞死亡与神经退行性疾病和癌症的关联表明了研究这种未充分研究的程序性细胞死亡形式的重要性。

DESCRIPTION (provided by applicant): Cell growth, division, and death are determinants of tissue and animal size, and defects in these fundamental cellular processes result in a variety of human disorders including cancer. The mechanistic relationship between growth and cell death is poorly defined in the context of normal animal development even though they have been the focus of many studies. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. We are studying steroid-activated autophagic programmed cell death during development of the fruit fly Drosophila melanogaster using larval salivary gland cell death as a model. An increase in steroid triggers a genetic hierarchy that activates nearly synchronous cell death in salivary glands. These developmentally-regulated cell deaths utilize apoptosis genes including caspase proteases, but salivary glands also possess the morphology of cells that die-by autophagic cell death. Mutations in caspases only partially inhibit salivary gland cell death, and our recent studies suggest an important relationship between steroid signaling, growth that is regulated by phosphoinositide 3 kinase (PI3K), and death of this tissue. Here we propose to: (1) determine the relationship between salivary gland growth and autophagic cell death during development, (2) determine how PI3K-induced growth influences steroid signaling and cell destruction mechanisms in dying salivary glands, and (3) identify new genes that function in autophagic cell death. The recent association of autophagic cell death with neurodegenerative disorders and cancer indicates the importance of investigating this understudied form of programmed cell death.