Restoring Melanocyte Stem Cells: A Model of Drug-Mediated Regeneration

恢复黑素细胞干细胞：药物介导的再生模型

• 批准号: 10253127
• 负责人: Melissa L Harris
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253127
• 关键词: Acute; Address; Age; Aging; Agonist; Attenuated; Biological; Birth; Body Surface; Cell Lineage; Cell physiology; Cells; Clinic; Cyclosporine; Defect; Disease; Drug Modelings; Elements; Environment; Evaluation; Event; Growth; Hair; Hair Color; Hair follicle structure; Hair shaft structure; Health; Hematopoietic System; Human; Hypopigmentation; Immunophilins; Impairment; In Situ; In Vitro; Individual; Intervention; Ionizing radiation; Length; Lesion; Life; Life Expectancy; Mediating; Methods; Minoxidil; Modeling; Molecular; Monitor; Mus; Natural regeneration; Organ; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Pigmentation physiologic function; Pigments; Pluripotent Stem Cells; Process; Production; Protocols documentation; Regenerative Medicine; Regenerative response; Regulatory Pathway; Rejuvenation; Risk; Skin; System; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissue Engineering; Tissues; Topical application; Transplantation; Visual; White Spots; Wild Type Mouse; Work; adult stem cell; age effect; age related; aged; base; cell type; clinical application; clinical development; experience; functional decline; gene therapy; in vivo; in vivo regeneration; insight; melanocyte; mouse model; novel; novel therapeutics; recruit; regenerative; repaired; screening; small molecule; stem cell population; stem cells; success; tacrolimus binding protein 4; tissue regeneration

Project Summary Increasing the length of time an individual experiences good health, or a healthy life expectancy, can be achieved by recovering tissue function that is lost or impaired due to aging or disease. Exploiting endogenous stem cells to repair or replace tissues in situ is an ideal approach to harness a body’s innate potential for rejuvenation. Unlike exogenous stem cells, using endogenous stem cells for regenerative medicine reduces the need for complicated, ex vivo cellular reprogramming and tissue engineering protocols, and eliminates the risk of rejection. Outside of the hematopoietic system, however, few examples exist where stem cell function is enhanced in situ for therapeutic purposes within the clinic. One reason for this is that although much is known about regulatory pathways that guide physiological stem cell function, much less is known about the minimum cellular and systemic requirements for tissue rejuvenation when the stem cell pool is damaged or absent. In addition, few pharmacological modulators have been identified to allow us to investigate this question in situ. Here we describe preliminary evidence demonstrating that we can reverse hair graying associated with melanocyte stem cell loss in mice using the novel drug RT1640. Hair graying and melanocyte stem cells are an ideal model for investigating tissue rejuvenation. Melanocyte stem cells reside in the hair follicle and are responsible for regenerating the pigment system and hair shaft pigmentation during hair growth. Gray hair due to loss of melanocyte stem cell function is both visible and non-lethal, melanocyte stem cell activation can be induced experimentally by simply plucking the hair, and this stem cell population is responsive to non-invasive therapeutics applied topically to the skin. Using this model, the aims of this proposal will address unanswered questions regarding pharmacologically induced in-situ tissue rejuvenation. Namely, we will identify the minimum biological elements necessary for in vivo repair, the critical cell types that participate in the regenerative response, and the key molecular processes targeted by this regenerative drug. We will answer these questions using a variety of hair graying mouse models with known molecular defects, in vivo fate mapping, and an in vitro histoculture method. These studies will provide a valuable new example of how tissue rejuvenation can be achieved through an in-situ approach, with significant relevance to understanding mechanisms involved in reversing the effects of disease and aging in humans.

项目摘要 增加个人体验身体健康或健康预期寿命的时间长度可能是 通过重新培养由于衰老或疾病而丢失或受损的组织功能实现。 干细胞修复或替换原位组织是利用身体的理想方法 与外源性干细胞不同，使用内源性干细胞恢复活力 需要复杂的，离体的地窖重编程和组织工程方案，并消除了您 拒绝风险。 为诊所内的治疗目的增强了原位。 关于指导生理干细胞功能的调节途径，对最小值的了解少得多 组织复兴的细胞和全身需求是干细胞库受损或不存在 此外，很少有人确定药理学模块，以使我们能够原位调查这个问题。 在这里，我们描述了预先限制的证据，表明我们可以逆转与 使用新型药物RT1640的小鼠中的黑色素细胞损失 研究组织恢复活力的理想模型。 负责在头发生长过程中再生色素系统和发轴色素沉着。 对于黑色素细胞干细胞功能的丧失既可见又不致死，黑素细胞干细胞的激活可以是 通过摘下头发来诱导实验，而该干细胞种群是对无创的反应 治疗方法局部应用于皮肤。 有关药理学引起的原位组织恢复活力的问题。 体内维修所需的最低生物学元素，关键细胞类型参与 再生反应以及该再生药物的关键分子过程 这些问题使用各种具有已知分子缺陷的灰色鼠标模型，体内命运 映射和一种植物培养方法。 可以通过An-Situ方法来实现恢复活力，并与理解相关 逆转疾病和衰老对人类的影响的机制。