Genetic control of Drosophila intestine stem cell self-renewal and proliferation

描述（由申请人提供）：在成人生活中，许多器官依靠干细胞在组织稳态或损伤反应中通过补充丢失的细胞来维持其完整性。成体干细胞的增殖和分化受到严格控制，以达到清除死细胞和产生新细胞之间的正常平衡。破坏潜在的调节机制可能导致干细胞/祖细胞过度增殖，导致肿瘤形成。果蝇成体中肠已成为研究干细胞增殖、自我更新和分化调控的一个有吸引力的模型，不仅因为该组织中的细胞谱系相对简单和明确，而且与哺乳动物系统相比，该系统利用了保守的遗传途径和调控机制。此外，复杂的遗传工具和丰富的试剂可以在果蝇群落中系统地识别和深入表征涉及肠干细胞（ISC）生物学的基因和途径。近年来，我们已经证明组织损伤刺激了果蝇中肠ISC的增殖和分化。我们已经确定胰岛素和河马（Hpo）信号通路是调节中肠稳态和再生的两个关键途径。由于这个系统相对较新，我们对ISC生物学的理解仍处于初级阶段。例如，中肠干细胞生态位的细胞和分子基础仍然是虚幻的。本研究的目的是确定控制果蝇中肠稳态和再生的新的遗传和分子成分，重点是控制ISC自我更新和增殖的调节机制。为此，我们启动了一项基因筛选，并确定了骨形态发生蛋白（BMP）和刺猬蛋白（Hh）通路中的成分对中肠再生至关重要。我们将研究BMP和Hh通路在正常组织稳态和损伤诱导再生过程中对ISC自我更新和增殖的调节作用。我们还将确定涉及中肠稳态和再生的其他调节因子。本课题的具体目标是：1)研究BMP信号在ISC自我更新调控中的功能和机制；2)研究中肠再生过程中BMP信号的调控及其与其他通路的相互作用；3)研究Hh信号在中肠稳态和再生中的作用；4)鉴定和表征参与中肠再生的新基因。这项研究将有助于更好地理解在成人组织稳态和再生过程中，外部信号和内在因素如何控制干细胞增殖、自我更新和分化。从这项研究中获得的知识将对癌症生物学和再生医学具有重要意义。

DESCRIPTION (provided by applicant): During adult life, many organs rely on stem cells to maintain their integrity by replenishing lost cells during tissue homeostasis or in response to injury. Proliferation and differentiation of adult stem cells are under tight control in order to achieve the normal balance between removing dead cells and producing new cells. Disruption of the underlying regulatory mechanisms could result in excessive proliferation of stem cells/progenitor cells, leading to tumor formation. The Drosophila adult midgut has emerged as an attractive model to investigate how stem cell proliferation, self-renewal and differentiation ar regulated, not only because the cell lineage in this tissue is relatively simple and well defined, but also because conserved genetic pathways and regulatory mechanisms are utilized in this system compared with mammalian systems. In addition, sophisticated genetic tools and the wealth of reagents available in the Drosophila community allow systematic identification and in-depth characterization of genes and pathways involved in intestine stem cell (ISC) biology. In recent years, we have demonstrated that tissue damage stimulates ISC proliferation and differentiation in Drosophila midgut. We have identified Insulin and Hippo (Hpo) signaling pathways as two critical pathways that regulate midgut homeostasis and regeneration. Because this system is relatively new, our understanding of ISC biology is still rudimentary. For example, the cellular and molecular basis of stem cell niche in the midgut has remained illusive. The goal of this research is to identify new genetic and molecular components that control Drosophila midgut homeostasis and regeneration with an emphasis on the regulatory mechanisms that control ISC self-renewal and proliferation. Toward this end, we have initiated a genetic screen and identified components in the Bone Morphogenic Protein (BMP) and Hedgehog (Hh) pathways as essential for midgut regeneration. We will investigate the function of BMP and Hh pathways in the regulation of ISC self-renewal and proliferation during normal tissue homeostasis and damage-induced regeneration. We will also identify other regulatory factors involved in midgut homeostasis and regeneration. The specific aims for this proposal are: 1) investigate the function and mechanism of BMP signaling in the regulation of ISC self-renewal; 2) investigate the regulation of BMP signaling and its interaction with other pathways in midgut regeneration; 3) investigate the role of Hh signaling in midgut homeostasis and regeneration; 4) identify and characterize new genes involved in midgut regeneration. The proposed study should provide better understanding of how extrinsic signals and intrinsic factors control stem cell proliferation, self-renewal and differentiation during adult tissue homeostasis and regeneration. The knowledge gained from this study will have important implications for cancer biology and regenerative medicine.