The coordination of cell death and corpse clearance

细胞死亡与尸体清除的协调

基本信息

批准号：
9894653
负责人：
Kimberly A McCall
金额：
$ 45.02万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

项目摘要

Project Summary Cell death is a fundamental process in animal development and homeostasis, and misregulation of cell death is associated with a large number of human diseases. Our research program aims to understand the diverse mechanisms of cell death, how dead cells are efficiently removed, and the physiological effects on organisms when these processes go awry. We study these questions in Drosophila, a model organism with exceptional genetic, genomic and cell biological tools. The research in this proposal focuses on four key questions. The first project investigates non-apoptotic cell death, which contributes significantly to development and disease, but is poorly understood. In the Drosophila ovary, germline-derived nurse cells undergo non-apoptotic programmed cell death as part of normal development. We have found that nurse cell death is controlled largely non-autonomously by the surrounding somatic follicle cells, and current work investigates the role of lysosomes and cell signaling in this process. A second major project investigates how dead cells are removed, particularly in tissues without access to circulating phagocytes such as macrophages. In many mammalian tissues, dead cells can be cleared by epithelial cells. In a Drosophila model for engulfment by epithelial cells, starvation induces degeneration of egg chambers, where the germline is engulfed by the surrounding epithelial follicle cells. This engulfment process happens synchronously and rapidly at the onset of cell death; however the genetic requirements for engulfment by epithelial cells are not well understood. In particular, how such non-professional phagocytes can improve their phagocytic capacity is not known, and our research program will reveal the requirements for engulfment by epithelial cells. A third project addresses how phagocytic cells can promote the death of their neighbors, through a newly described type of cell death called phagoptosis. In the fourth project, we investigate the consequences of persisting cell corpses in the ovary and the brain, and how defective phagocytosis can affect disease progression. We will examine the global changes to organisms with defective cell death or phagocytosis and how defective phagocytosis interacts with genetic models of human disease. Given the high degree of conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly will provide insight into the diversity of cell death mechanisms and consequences of defective cell removal in humans. These studies may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer.

项目摘要细胞死亡是动物发育和稳态的一个基本过程，也是不调节细胞死亡与大量人类疾病有关。我们的研究计划的目的要了解细胞死亡的多种机制，如何有效去除死细胞，当这些过程出现问题时，对生物的生理影响。我们研究这些果蝇的问题，果蝇，一种模型生物，具有特殊的遗传，基因组和细胞生物学工具。该提案中的研究集中在四个关键问题上。第一个项目调查非凋亡细胞死亡，对发育和疾病产生了重要贡献，但理解不佳。在果蝇卵巢中，种系衍生的护士细胞发生非凋亡程序性细胞死亡是正常发育的一部分。我们发现护士细胞死亡是周围的体细胞细胞在很大程度上是非自主的，并且目前的工作研究溶酶体和细胞信号在此过程中的作用。第二个主要项目研究如何去除死细胞，尤其是在没有循环的组织中吞噬细胞，例如巨噬细胞。在许多哺乳动物组织中，可以通过上皮细胞。在上皮细胞吞噬的果蝇模型中，饥饿会诱导鸡蛋室的变性，该种系被周围的上皮吞没卵泡细胞。这种吞噬过程在细胞发作时同步和快速地发生死亡;但是，上皮细胞吞噬的遗传要求不好理解。特别是，这种非专业吞噬细胞如何改善其吞噬细胞能力尚不清楚，我们的研究计划将揭示上皮细胞。第三个项目解决了吞噬细胞如何促进其死亡邻居通过新描述的细胞死亡类型，称为吞噬作用。在第四个项目中，我们研究了卵巢和大脑中持续的细胞尸体的后果，以及如何吞噬作用有缺陷会影响疾病进展。我们将研究全球变化细胞死亡或吞噬作用有缺陷的生物以及缺陷的吞噬作用如何相互作用与人类疾病的遗传模型。鉴于细胞死亡的高度保护到目前为止，果蝇和哺乳动物之间的机制，我们期望途径我们在飞行中发现将洞悉细胞死亡机制的多样性和人类中切除细胞有缺陷的后果。这些研究可能揭示了新的治疗性细胞死亡过多或不足的疾病（例如神经退行性）的靶标疾病和癌症。