Apoptosis and Fibrosis

细胞凋亡和纤维化

• 批准号: 8525631
• 负责人: Ariel R Johnson
• 金额: $ 2万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2014-01-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525631
• 关键词: Alveolar; Antibody Formation; Apoptosis; Apoptotic; Bleomycin; Blocking Antibodies; Blood Vessels; Camptothecin; Cardiac; Cell Death; Cells; Characteristics; Cicatrix; Collagen; Collagen Type I; Conditioned Culture Media; Cosmetics; Data; Dermal; Development; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Face; Fibroblasts; Fibrosis; Gene Expression; Goals; Harvest; Healed; Health; Heart; Hepatic; Hepatocyte; Human; Immunohistochemistry; In Vitro; Individual; Injection of therapeutic agent; Interstitial Collagenase; Jaw; Kidney; Lesion; Limb structure; Link; Liver; Liver Fibrosis; Lung; Measurement; Measures; Mediator of activation protein; Modeling; Monitor; Mucous Membrane; Myofibroblast; Oral Stage; Oral mucous membrane structure; Organ; Outcome; Paracrine Communication; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Plastics; Play; Process; Radiation; Reaction; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Skin; System; TIMP1 gene; Therapeutic; Therapeutic Intervention; Tissues; Toxin; Trauma; Wound Healing; angiogenesis; craniofacial; experience; healing; improved; in vivo; injury and repair; intradermal injection; prevent; psychologic; public health relevance; response; vascular bed; wound

DESCRIPTION (provided by applicant): Tissue fibrosis can be caused by radiation, trauma, medications, or toxins, and fibrosis can occur anywhere in the body including the oral mucosa, lung, kidney, liver, and skin. One characteristic of fibrosis is an increase in the synthesis of collagen type I (COL1) and decreases in both synthesis of COL3 and degradation of COL1. The presence of contractile fibroblasts (FB), termed myofibroblasts (myoFB), is considered a hallmark of the fibrotic response. Another hallmark of fibrosis is increased cell death of hepatocytes, alveolar epithelial cells, and endothelial cells (ECs). The level of apoptosis and degree of fibrosis have been related in hepatic, pulmonary, and renal fibrosis, suggesting that apoptotic cells directly influence the development of fibrosis. The mechanisms that dictate the interaction of apoptotic cells and fibrosis are poorly understood. EC apoptosis is a prominent feature in the latter stages of oral and dermal wound healing, as apoptosis is requisite to the pruning of the robust vascular bed that is produced during wound healing. The presence of high levels of apoptotic ECs in the resolving wound suggests that endothelial-fibroblast interactions may play a role in scarring and fibrotic outcomes. In renal, hepatic, and bleomycin-induced fibrosis, potent paracrine signaling factors secreted by apoptotic ECs have been identified. These factors can act directly on FBs to induce proliferation, myoFB differentiation, and collagen synthesis. We hypothesize that apoptotic ECs contribute to fibrosis and scar formation by secreting factors that increase dermal myoFB differentiation, collagen synthesis, and FB proliferation, while decreasing collagen degradation in FBs. The current research will provide the first examination of the mechanism of interaction between apoptotic ECs and FBs in dermal fibrosis. Aim 1 will establish a role for apoptotic EC as mediators of fibrosis in vivo. In vivo, te effect of apoptotic ECs will be examined by monitoring myoFB differentiation, collagen synthesis, and FB proliferation following intradermal injection of apoptotic ECs or their secreted factors. Aim 2 will determine the mechanism of interaction between apoptotic ECs and FB function in vitro. Normal human dermal FBs will be exposed to conditioned media from apoptotic ECs. The fibrogenic response and downstream signaling will be examined. Throughout the experimental plan, the fibrogenic response will be assessed by determining the ratios of COL1:COL3 and MMP1:TIMP1, both known characteristics of a fibrotic reaction. The long term goal of the proposed research is to uncover the mechanisms that influence scar formation and fibrosis in skin. This project has the potential to have a significant impact on the understating o fibrosis in scar formation as well as other related conditions, such as renal, hepatic, pulmonary, and cardiac fibrosis. Elucidation of these mechanisms will identify opportunities for therapeutic intervention in fibrosis.

描述（由申请人提供）：组织纤维化可由辐射、创伤、药物或毒素引起，纤维化可发生在身体的任何部位，包括口腔粘膜、肺、肾、肝和皮肤。纤维化的一个特征是I型胶原蛋白（COL1）的合成增加，COL3的合成和COL1的降解减少。收缩性成纤维细胞（FB）（称为肌成纤维细胞（myofibroblasts，myoFB））的存在被认为是纤维化反应的标志。纤维化的另一个标志是肝细胞、肺泡上皮细胞和内皮细胞（EC）的细胞死亡增加。在肝、肺和肾纤维化中，凋亡水平与纤维化程度相关，表明凋亡细胞直接影响纤维化的发展。决定凋亡细胞和纤维化的相互作用的机制知之甚少。EC细胞凋亡是口腔和皮肤伤口愈合后期的一个突出特征，因为细胞凋亡是修剪伤口愈合期间产生的强健血管床所必需的。高水平的凋亡内皮细胞在解决伤口的存在表明，内皮细胞成纤维细胞的相互作用可能在瘢痕形成和纤维化的结果中发挥作用。在肾、肝和博莱霉素诱导的纤维化中，已经鉴定出由凋亡EC分泌的有效旁分泌信号因子。这些因子可以直接作用于FB以诱导增殖、myoFB分化和胶原合成。我们假设凋亡的内皮细胞通过分泌增加真皮myoFB分化、胶原合成和FB增殖的因子，同时减少FB中的胶原降解，从而促进纤维化和瘢痕形成。目前的研究将提供第一次检查的机制之间的相互作用凋亡内皮细胞和纤维母细胞在真皮纤维化。目的1将建立凋亡EC作为体内纤维化介质的作用。在体内，通过皮内注射凋亡EC或其分泌因子后监测myoFB分化、胶原合成和FB增殖来检查凋亡EC的作用。目的2探讨凋亡内皮细胞与FB功能相互作用的机制。将正常人真皮FB暴露于来自凋亡EC的条件培养基。将检查纤维化反应和下游信号传导。在整个实验计划中，将通过确定C0L 1：C0L 3和MMP 1：TIMP 1的比率来评估纤维化反应，这两种比率均为纤维化反应的已知特征。这项研究的长期目标是揭示影响皮肤瘢痕形成和纤维化的机制。该项目有可能对瘢痕形成中的纤维化以及其他相关疾病（如肾、肝、肺和心脏纤维化）产生重大影响。阐明这些机制将确定纤维化治疗干预的机会。