Induction of Programmed Cell Death by cellular Mis-specification

描述（由申请人提供）：这里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范和细胞分化。然而，干扰细胞命运和细胞功能的建立可导致细胞死亡的诱导。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移除，它们可能会导致癌症等恶性肿瘤。然而，在病理条件下，同样的策略可能导致细胞的不适当死亡，从而在发育过程中产生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细胞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。没有接收到发育信号或发育信号不正确的细胞死亡的原因尚不清楚。在遗传模式生物黑腹果蝇中，存在许多突变体，这些突变体阻断了正常的细胞规范和分化。随后，这些细胞经历细胞死亡。因此，这些突变体为研究这种形式的细胞死亡的调控和开始提供了一个很好的遗传模型。我们已经确定，细胞不规范是这些突变体细胞死亡的潜在原因。细胞死亡诱导基因hid在错误指定的细胞中特异性上调，这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常发育的能力。如果细胞没有做到这一点，监控机制就会触发hid的转录诱导并诱导细胞死亡。为了从遗传和分子上表征假设的监测机制，我们将(1)分析hid基因的启动子，并确定在错误规范下与之结合的因子，(2)分析在错误规范诱导的细胞死亡的微阵列分析中发现的一些基因的遗传需求，以及(3)进行遗传筛选以确定这一过程所需的基因。本提案的目标是全面了解这一有趣的生物学现象背后的机制，并将这些知识用于治疗目的。

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.