Induction of Programmed Cell Death by cellular Mis-specification

描述（由申请人提供）：本文提出的工作旨在阐明未能采用适当命运的细胞诱导程序性细胞死亡的机制。正常的发育和体内平衡需要适当的规格和细胞分化。然而，干扰细胞命运和细胞功能的建立可导致诱导细胞死亡。这种策略可能会保护生物体免受发育错误的影响，因为如果这些细胞不被去除，它们可能会导致恶性肿瘤，如癌症。然而，在病理条件下，相同的策略可能导致细胞的不适当死亡，从而在发育期间引起先天性缺陷或其他条件，如神经退行性疾病。因此，对潜在机制的详细研究将为已知发生凋亡失调的人类疾病提供新的见解，并可能导致新的治疗干预策略。目前还不清楚为什么一个细胞死亡，没有收到或不正确的发育信号。在遗传模式生物黑腹果蝇（Drosophila melanogaster）中，存在许多阻断正常细胞特化和分化的突变体。随后，这些细胞经历细胞死亡。因此，这些突变体提供了一个很好的遗传模型来研究这种形式的细胞死亡的调控和发病。我们已经确定细胞的错误指定是这些突变体细胞死亡的根本原因。细胞死亡诱导基因HID在错误指定的细胞中特异性上调，表明错误指定诱导的细胞死亡是一个活跃的基因导向过程的结果。我们假设有一种机制监控着细胞正确发育的能力。如果细胞不能做到这一点，监控机制就会触发hid的转录诱导并诱导细胞死亡。为了从遗传学和分子学上表征假定的监测机制，我们将（1）分析hid基因的启动子并鉴定与其结合以响应错误指定的因子，（2）分析在微阵列分析中鉴定的用于错误指定诱导的细胞死亡的许多基因的遗传要求，和（3）进行遗传筛选以鉴定该过程所需的基因。这一建议的目标是全面了解这一有趣的生物学现象的机制，并利用这一知识进行治疗。 该项目研究了细胞在没有收到正确的发育信息时死亡的机制。这些被错误告知的细胞类似于癌细胞，观察到它们死亡可能会保护生物体免受几种常见疾病的侵害。了解这一过程的机制可能会导致新的癌症治疗干预措施，也可能与神经退行性疾病的治疗有关。

DESCRIPTION (provided by applicant): The work proposed here is intended to elucidate the mechanisms by which cells that fail to adopt appropriate fate induce programmed cell death. Normal development and homeostasis requires proper specification and cellular differentiation. However, interference with the establishment of cellular fates and cellular functions can lead to the induction of cell death. This strategy might guard the organism against developmental errors, because if these cells were not removed, they might cause malignancies such as cancer. However, under pathological conditions the same strategy may cause the inappropriate death of cells giving rise to congenital defects during development or other conditions such as neurodegenerative disorders. Thus, a detailed investigation of the underlying mechanisms will provide new insights into human diseases in which deregulation of apoptosis is known to occur and may lead to new strategies for therapeutic intervention. It is unknown why a cell dies that receives no or an incorrect developmental signal. In the genetic model organism Drosophila melanogaster, a number of mutants exist that block normal cellular specification and differentiation. Subsequently, these cells undergo cell death. Thus, these mutants provide an excellent genetic model to study the regulation and onset of this form of cell death. We have determined that cellular mis- specification is the underlying cause of cell death in these mutants. The cell death-inducing gene hid is specifically up-regulated in mis-specified cells, suggesting that mis-specification-induced cell death is the result of an active gene-directed process. We postulate that a mechanism monitors the cell's ability to develop correctly. If the cell fails to do so, the monitoring mechanism triggers the transcriptional induction of hid and induces cell death. To genetically and molecularly characterize the postulated monitoring mechanism we will (1) analyze the promoter of the hid gene and identify the factor(s) binding to it in response to mis-specification, (2) analyze the genetic requirement of a number of genes identified in a microarray analysis for mis- specification-induced cell death, and (3) perform genetic screens to identify genes which are required for this process. It is the goal of this proposal to gain a comprehensive understanding of the mechanisms underlying this interesting biological phenomenon, and to exploit this knowledge for therapeutic purposes. This project investigates the mechanisms by which cells die if they do not receive the correct developmental information. These incorrectly informed cells resemble cancer cells, and the observation that they die may protect the organism from several common diseases. Understanding the mechanisms of this process may lead to new therapeutic interventions for cancer, and may also be relevant for treatment of neurodegenerative diseases.