ADAM10 in Intestinal Homeostasis and Regeneration

ADAM10 在肠道稳态和再生中的作用

• 批准号: 8371729
• 负责人: PETER J DEMPSEY
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371729
• 关键词: Address; Adult; Affect; American; Applications Grants; Biology; Cell Lineage; Cell Proliferation; Cell surface; Cells; Chronic; Chronic Disease; Clinical; Data; Diarrhea; Disease; Disintegrins; Environment; Event; Failure; Goals; Grant; Homeostasis; Human; Inborn Genetic Diseases; Inflammatory Bowel Diseases; Injury; Intervention; Intestinal Diseases; Intestines; Knowledge; Knowledge acquisition; Lead; Mediating; Metalloproteases; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Natural regeneration; Outcome; Pathway interactions; Patients; Play; Population; Proliferating; Public Health; Quality of life; Regenerative Medicine; Regulation; Research; Role; Signal Transduction; Signaling Molecule; Stem Cell Research; Stem cells; Testing; Therapeutic; Work; base; cell injury; extracellular; gastrointestinal; improved; injury and repair; innovation; interest; intestinal crypt; notch protein; novel therapeutic intervention; novel therapeutics; prevent; progenitor; programs; regenerative; response; secretase; stem cell biology; stem cell niche; stem cell population; stem cell therapy; therapeutic target

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. PUBLIC HEALTH RELEVANCE: Human intestinal diseases comprise a wide variety of pathological states such as IBD that are a significant and ongoing public health burden. The disintegrin-metalloproteinase ADAM10 is an ectodomain sheddase that allows cells to respond to their extracellular environment through regulation of cell surface signaling molecules. We hypothesize that ADAM10 acts iteratively to maintain intestinal crypt homeostasis. The aims of this grant proposal are to assess the extent to which ADAM10 regulates adult intestinal stem cells during normal intestinal homeostasis and under conditions of injury and repair, as well as to delineate the role of ADAM10 signaling in progenitor cell proliferation and lineage specification. A detailed understanding of ADAM10 signaling in the intestine is expected to lead to new therapeutic interventions for regenerative medicine and the treatment of human intestinal diseases.

描述（由申请人提供）：人类肠道疾病由多种病理状态组成，包括炎症性肠病（IBD）和肠衰竭等慢性疾病，因此构成了重大的公共卫生负担。因此，肠道研究的一个主要挑战是对肠道生物学有更详细的了解，这将导致采取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 (ISC) 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。这笔赠款的目的是确定 ADAM10 是一种 α 分泌酶（即胞外域脱落酶），预计可调节关键的细胞外信号传导事件，包括干细胞生态位内 ISC 及其后代中的 Notch 信号传导。我们的中心假设是，ADAM10 在成体隐窝中的多个水平上发挥作用，以维持 ISC 并控制祖细胞增殖和谱系规范，并且这些相同的信号在肠道损伤和再生过程中发挥着关键作用。我们的假设是根据我们使用肠道特异性 ADAM10 缺陷小鼠的初步数据得出的。拟议研究的基本原理是，通过了解 ADAM10 信号传导在正常肠道稳态期间维持 ISC/祖细胞群以及损伤/再生模型中的作用，我们将 ADAM10 定义为新的分子靶标，从而为再生医学中的干细胞疗法和肠道疾病的治疗提供创新方法。在目标 1 中，我们将通过细胞谱系追踪来定义不同 ISC 群体中 ADAM10 的要求。在目标 2 中，我们将确定不同 ISC 群体在肠道损伤/再生中对 ADAM10 的需求。在目标 3 中，我们将使用条件 ADAM10 缺陷小鼠确定 ADAM10 在祖细胞增殖和细胞谱系规范中的作用。在这些研究结束时，我们将扩展我们对正常和再生条件下肠道稳态期间 ADAM10 信号在 ISC 群体中重要性的认识，评估其对祖细胞增殖和细胞命运决定调节的贡献，并确定 ADAM10 介导的 Notch 信号在这些事件中的重要性。 公共卫生相关性：人类肠道疾病包括多种病理状态，例如炎症性肠病（IBD），这是一个重大且持续的公共卫生负担。解整合素金属蛋白酶 ADAM10 是一种胞外域脱落酶，可让细胞通过调节细胞表面信号分子来响应细胞外环境。我们假设 ADAM10 反复发挥作用以维持肠隐窝稳态。该拨款提案的目的是评估 ADAM10 在正常肠道稳态期间以及损伤和修复条件下调节成体肠道干细胞的程度，以及描述 ADAM10 信号传导在祖细胞增殖和谱系规范中的作用。对肠道中 ADAM10 信号传导的详细了解有望为再生医学和人类肠道疾病的治疗带来新的治疗干预措施。