ADAM10 in Intestinal Homeostasis and Regeneration

描述（由申请人提供）：人类肠道疾病由多种病理状态组成，包括慢性疾病，如炎症性肠病（IBD）和肠衰竭，因此代表了重大的公共卫生负担。因此，肠道研究的一个主要挑战是更详细地了解肠道生物学，这将导致新的干预措施来预防和治疗这些使人衰弱的肠道疾病。我研究的长期目标是了解调节肠道干细胞（ISCs）的分子机制，以及如何将这些途径用于再生医学或调节以改善患有这些慢性疾病的患者的临床结果和生活质量。这项补助金的目的是确定以下方面的作用： ADAM 10是一种α-分泌酶（即，胞外域脱落酶），其被预测调节关键的细胞外信号传导事件，包括干细胞生态位内的ISC及其后代中的Notch信号传导。我们的中心假设是，ADAM 10在成年隐窝中以多个水平起作用，以维持ISCs并控制祖细胞增殖和谱系特化，并且这些相同的信号在肠损伤和再生期间起关键作用。我们的假设是基于我们自己的初步数据，使用精氨酸特异性ADAM 10缺陷小鼠。这项研究的基本原理是，通过了解ADAM 10信号在维持正常肠道稳态和损伤/再生模型中的ISC/祖细胞群体中的作用，我们将把ADAM 10定义为一个新的分子靶点，从而为再生医学和肠道疾病的治疗提供干细胞疗法的创新方法。在目标1中，我们将通过细胞谱系追踪来确定不同ISC人群对ADAM 10的要求。在目标2中，我们将确定肠损伤/再生中不同ISC群体对ADAM 10的需求。在目标3中，我们将使用条件性ADAM 10缺陷小鼠确定ADAM 10在祖细胞增殖和细胞谱系特化中的作用。在这些研究的结论，我们将扩大我们的知识在正常和再生条件下的肠稳态期间的ADAM 10信号在ISC群体中的重要性，评估其对祖细胞增殖和细胞命运决定的调节的贡献，并确定在这些事件中的ADAM 10介导的Notch信号的意义。

DESCRIPTION (provided by applicant): Human intestinal diseases are comprised of a wide variety of pathological states, including chronic illnesses such as inflammatory bowel disease (IBD) and intestinal failure, and thus represent a significant public health burden. A major challenge for intestinal research therefore is to develop a more detailed understanding of intestinal biology that will lead to new interventions to prevent and treat these debilitating intestinal diseases. The long-term goals of my research are to understand the molecular mechanisms that regulate intestinal stem cells (ISCs), and how these pathways can be utilized for regenerative medicine or modulated to improve clinical outcomes and quality of life of patients suffering these chronic illnesses. The objective of this grant is to determine the role of ADAM10, which is an a-secretase (i.e., ectodomain sheddase) that is predicted to regulate key extracellular signaling events, including Notch signaling in ISCs and their progeny within the stem cell niche. Our central hypothesis is that ADAM10 acts at multiple levels in adult crypts to maintain ISCs and to control progenitor proliferation and lineage specification, and that these same signals play a critical role during intestinal injury and regeneration. Our hypothesis has been formulated on the basis of our own preliminary data us- ing intestine-specific ADAM10-deficient mice. The rationale for the proposed research is that, by understanding the role for ADAM10 signaling in maintaining ISCs/progenitor populations during normal intestinal homeostasis, and in models of injury/regeneration, we will define ADAM10 as a new molecular target, resulting in innovative approaches for stem cell therapies in regenerative medicine and for treatment of intestinal diseases. In Aim 1, we will define the requirements for ADAM10 in distinct ISC populations through cell lineage tracing. In Aim 2, we will determine the requirements for ADAM10 in distinct ISC population in intestinal inju- ry/regeneration. In Aim 3, we will determine the role of ADAM10 in progenitor proliferation and cell lineage specification using conditional ADAM10-deficient mice. At the conclusion of these studies, we will have expanded our knowledge on the importance of ADAM10 signaling in ISC populations during intestinal homeosta- sis under normal and regenerative conditions, evaluated its contribution to the regulation of progenitor cell proliferation and cell fate decisions, and determined the significance of ADAM10-mediated Notch signaling in these events.