ADAM10 in Intestinal Homeostasis and Regeneration

描述(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)和肠道衰竭，因此是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令人衰弱的肠道疾病。我研究的长期目标是了解调节肠道干细胞(ISCs)的分子机制，以及这些途径如何被用于再生医学或如何被调节以改善这些慢性病患者的临床结果和生活质量。这笔赠款的目的是确定 ADAM10，这是一种α-分泌酶(即胞外结构域脱落酶)，被预测调节关键的细胞外信号事件，包括ISCs及其子代干细胞内的Notch信号。我们的中心假设是，ADAM10在成人隐窝中发挥多个水平的作用，以维持ISCs，并控制祖细胞的增殖和谱系特征，这些相同的信号在肠道损伤和再生过程中发挥关键作用。我们的假设是基于我们自己对肠道特异性ADAM10缺陷小鼠的初步数据提出的。这项研究的理论基础是，通过了解ADAM10信号在正常肠道内稳期间维持ISCs/前体细胞数量以及在损伤/再生模型中的作用，我们将把ADAM10定义为一个新的分子靶点，从而为再生医学中的干细胞治疗和肠道疾病的治疗创造出创新的方法。在目标1中，我们将通过细胞谱系追踪来定义不同ISC人群对ADAM10的需求。在目标2中，我们将确定不同ISC人群在肠道损伤/再生中对ADAM10的需求。在目标3中，我们将使用条件性ADAM10缺陷小鼠来确定ADAM10在祖细胞增殖和细胞谱系指定中的作用。在这些研究的结论中，我们将扩大我们对ADAM10信号在正常和再生条件下肠道内稳态期间ISC群体中的重要性的认识，评估其在祖细胞增殖和细胞命运决定中的调节作用，并确定ADAM10介导的Notch信号在这些事件中的意义。

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.