New upstream targets for HIF-1a-mediated regeneration in young and aged animals

HIF-1a 介导的年轻和老年动物再生的新上游靶标

• 批准号: 10589328
• 负责人: Georgios Hajishengallis
• 金额: $ 76.62万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589328
• 关键词: AMD3100; Affect; Agonist; Animals; Anti-Inflammatory Agents; Biocompatible Materials; Bone Regeneration; Bone Tissue; Bone remodeling; Breeding; CXCR; CXCR4 gene; Cartilage; Cell Count; Defect; Dental; Development; Disease; Disease model; Distal; Dose; Drug Delivery Systems; Drug Modulation; Ear; Evolution; G-Protein-Coupled Receptors; Gel; Genetic Transcription; Grant; Hair follicle structure; Health; Hydrogels; Hypoxia Inducible Factor; Immune response; In Situ; Individual; Inflammation; Inflammatory; Injectable; Injections; Injury; Intervention; Jaw; Laboratories; Lesion; Ligature; Mammals; Mediating; Medicine; Messenger RNA; Metabolic; Modeling; Molecular; Mus; Mussels; Myeloid Cells; Natural regeneration; Newts; Osteoblasts; PAR-1 Receptor; Pathway interactions; Patients; Peptides; Periodontal Diseases; Periodontal Ligament; Periodontitis; Pharmaceutical Preparations; Polyethylene Glycols; Polymers; Predisposition; Prevalence; Prodrugs; Proteinase-Activated Receptors; Proteins; Regenerative response; Regulation; Regulatory T-Lymphocyte; Resolution; Role; Series; Severities; Site; System; T memory cell; Testing; Thrombin; Tissues; Tooth Loss; Translations; Up-Regulation; Work; aged; antagonist; bioscaffold; bone; cytokine; design; economic impact; experimental study; healing; human old age (65+); immunoregulation; in vivo; inhibitor; local drug delivery; new therapeutic target; novel; novel therapeutics; oral tissue; regenerative; regenerative therapy; response; self assembly; small hairpin RNA; small molecule; soft tissue; stem cell population; stem cells; subcutaneous; tissue regeneration; trait; wound healing; young adult

Project Summary/Abstract The ability to regenerate tissue in mammals has remained elusive. While the use of stem cell populations in the context of bio-scaffolds has shown promise as a potential means of replacing lost, damaged, or diseased tissue, significant challenges remain. An alternative approach is to attempt to evoke a classical in situ regenerative response emulating that seen in lower species such as newts. While this trait was thought to be lost in evolution, our observation (Heber-Katz) that the MRL mouse and related strains have a significant spontaneous regenerative capability demonstrates that the trait is retained in mammals. Studies over the past almost 25 years have culminated in the identification of the HIF-1 (hypoxia inducible factor) pathway as the central actor regulating regeneration in mice. The up-regulation of HIF-1 in non-regenerating mice have allowed these mice to regenerate ear holes with cartilage and hair follicles; and jaw bone and associated soft tissues after induced periodontal disease (PD). In both cases, a classical regenerative de-differentiation response was seen. This was achieved using the PHD inhibitor 1,4-DPCA in novel injectable biomaterial constructs (Messersmith) leading to the stabilization of high levels of HIF-1 in vivo. The mechanisms that were identified in the PD model involved inflammatory cytokines, bone remodeling osteoblasts, Tregs and CXCR4 expression. Using a CXCR antagonist, AMD3100, the regenerative response could be blocked and supports the need for Tregs and certain stem and myeloid cells. In this current proposal, we provide preliminary results showing that two new upstream target molecules DEL-1 (Hajishengallis) and PAR1 (Heber-Katz) with known agonists have been identified which affect HIF-1 expression. We will explore the role of HIF-1 and these two molecules in the regenerative response in young and aged mice using both the ear hole model and the PD model. We will use advanced molecular design to produce a biomaterial capable of achieving single dose and local delivery vs the current three dose delivery system. In addition to yielding a novel soft and bone tissue regeneration therapy, we believe that this system provides an impressive landscape of phenomena that will yield important mechanistic information about in-situ regenerative responses in oral tissues. In Aim 1, we will create new biomaterials to yield local drug release using mucoadhesive polymers; in Aim 2, we will examine the role of the anti-inflammatory molecular DEL-1 in aged mice with PD, a molecule having direct affects on HIF-1 levels; and in Aim 3, we will examine the role of PAR1, another molecule which affects HIF-1 levels in the ear hole and periodontal injury models, in both young and aged mice.

项目总结/摘要 哺乳动物的组织再生能力仍然难以捉摸。虽然使用干细胞群体在 生物支架作为一种替代丢失、损坏或患病的潜在手段， 组织，仍然存在重大挑战。另一种方法是试图唤起一个经典的现场 再生反应模仿在低等物种如蝾螈中看到的。虽然这种特性被认为是 我们的观察（Heber-Katz）表明，MRL小鼠和相关品系具有显著的 自发再生能力证明了这种特性在哺乳动物中得以保留。过去的研究 近25年来，HIF-1 α（缺氧诱导因子）通路被鉴定为 调节小鼠再生的中枢因子。HIF-1 α在非再生小鼠中的上调， 让这些老鼠用软骨和毛囊再生耳洞，颌骨和相关的软组织， 组织诱导牙周病（PD）。在这两种情况下，典型的再生去分化 看到了回应。这是在新型可注射生物材料中使用PHD抑制剂1，4-DPCA实现的 构建体（Messersmith），导致体内高水平HIF-1 α的稳定。的机制 在PD模型中鉴定了涉及炎性细胞因子、骨重建成骨细胞、TGFAP和 CXCR 4表达。使用CXCR拮抗剂AMD 3100，再生反应可以被阻断， 支持了对TGFAP和某些干细胞和骨髓细胞的需求。 在目前的建议中，我们提供的初步结果表明，两个新的上游目标， 已经鉴定了具有已知激动剂的分子DEL-1（Hajishengallis）和PAR 1（Heber-Katz）， 影响HIF-1 α表达。我们将探讨HIF-1 α和这两种分子在再生性肿瘤中的作用。 使用耳孔模型和PD模型在年轻和老年小鼠中的反应。 我们将使用先进的分子设计来生产能够实现单剂量的生物材料 和局部给药相对于目前的三剂量给药系统。除了产生一种新的软组织和骨组织， 再生疗法，我们相信这个系统提供了令人印象深刻的现象景观，将 产生关于口腔组织中原位再生反应的重要机制信息。 在目标1中，我们将创造新的生物材料，使用粘膜粘附聚合物产生局部药物释放;在目标2中， 我们将研究抗炎分子DEL-1在患有PD的老年小鼠中的作用， 直接影响HIF-1 α水平;在目标3中，我们将研究PAR 1的作用，PAR 1是另一种影响HIF-1 α水平的分子。 在年轻和老年小鼠的耳孔和牙周损伤模型中的HIF-1 β水平。