THE USE OF FIBRIN HYDROGELS TO PROMOTE SALIVARY GLAND REGENERATION

使用纤维蛋白水凝胶促进唾液腺再生

基本信息

批准号：
10457818
负责人：
Stelios Theoharis Andreadis
金额：
$ 73.63万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457818
关键词：
3-Dimensional Acinar Cell Activities of Daily Living Address American Cancer Society Blocking Antibodies Blood Vessels Cell Proliferation Cell Separation Cell Survival Cell-Matrix Junction Cells Conditioned Culture Media Deglutition Development Effectiveness Epithelial FGF10 gene Fibrin Food Gland Growth Factor Hair follicle structure Head and Neck Cancer Head and neck structure Human Hydrogels Immobilization Impairment In Vitro Infection Light Link Maintenance Mastication Measures Mesenchymal Stem Cells Methods Morphogenesis Mus Natural regeneration Nerve Oral Pathway interactions Patients Peptides Persons Pharmaceutical Preparations Physiology Polymers Production Radiation therapy Recombinant Fusion Proteins Recovery of Function Residual state Saliva Salivary Salivary Glands Secretory Vesicles Signal Transduction Speech Structure Surface Symptoms System Taste Perception Therapeutic Intervention Tight Junctions Tissues United States Vascular Endothelial Growth Factors Vascularization Water Work Xerostomia alternative treatment cell assembly cell motility crosslink design fibroblast growth factor 9 head and neck cancer patient hydrogel scaffold in vivo irradiation keratinocyte growth factor laminin-1 microbial migration mouse model nerve supply neurotrophic factor oral mucositis polymerization preservation response saliva secretion scaffold targeted treatment tyrosyl-isoleucyl-glycyl-seryl-arginine wound healing

项目摘要

ABSTRACT According to the American Cancer Society, more than 60,000 people will develop head and neck cancer this year and those patients must receive radiation therapy to survive. This treatment regularly destroys the salivary glands (SG), leading to a loss of secretory function which is typically permanent. Current treatments remain largely ineffective, with therapeutic interventions being limited to use of saliva substitutes with modest effectiveness and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore SG functioning is essential. In response to the challenges noted above, we propose introduction of FGF7 and FGF10, both of which activate FGF2b signaling to promote SG epithelial morphogenesis and differentiation (Aims 1 and 2, in vitro and in vivo, respectively). Having fortified our scaffold to enhance SG morphogenesis and differentiation, we will nonetheless still be faced with absent or poorly developed vasculature and nerve systems, as indicated by repeated studies demonstrating loss of vascularization and innervation in irradiated SG. In response to these challenges, we will draw on our previous findings indicating VEGF and FGF9 to aid vascular formation and neurotrophic factors (e.g., NGF) to promote innervation (Aim 3). We hypothesize that a modified FH scaffold containing immobilized L1 peptides (L1p) and GF (L1p-GF-FH) will promote formation of functional tissue in irradiated SG. Aim 1: will demonstrate sustained secretory function using a fortified scaffold in vitro. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in irradiated SG. Aim 2: will demonstrate sustained secretory function using a fortified scaffold in vivo. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in an irradiated SMG mouse model. Aim 3: will restore full functionality to irradiated SG in vivo. We will combine our Ep-FH scaffold with polymeric microparticles to release pro-angiogenic and pro-innervation GF in a temporal sequence, mimicking the in vivo physiology, to enhance functional recovery of SMG following radiation treatment. In summary, our proposed studies will extend our findings to date using L1p to restore SG function, thereby allowing for both greater sustainability and a deeper degree of functionality.

抽象的根据美国癌症协会的数据，有60,000多人将发展头颈癌年份和这些患者必须接受放射治疗才能生存。这种治疗定期破坏唾液腺体（SG），导致分泌功能的丧失，通常是永久性的。目前的治疗仍然存在在很大程度上无效，治疗性干预措施仅限于使用适度的唾液替代品仅提供暂时缓解的有效性和药物。鉴于高度的需求和当前疗法的局限性，恢复SG功能的替代疗法的开发至关重要。在对上述挑战的回应，我们提出了FGF7和FGF10的引入，这两者都激活 FGF2B信号传导促进SG上皮形态发生和分化（目标1和2，体外和体内，分别）。加强了我们的支架以增强SG的形态发生和分化，我们将尽管如此反复研究表明，辐射的SG中血管化和神经支配的丧失。回应这些挑战，我们将借鉴以前的发现，表明VEGF和FGF9有助于血管形成和神经营养因子（例如NGF）促进神经（目标3）。我们假设修改了FH脚手架含有固定的L1肽（L1P）和GF（L1P-GF-FH）将促进在功能组织中形成辐照的SG。 AIM 1：将在体外使用强化的支架展示持续的分泌功能。我们将确定将FGF7和FGF10掺入L1P-FH（称为EP-FH）脚手架是否可以分泌在辐照的SG中，保持完整的持续时间保持完整。目标2：将展示持续的分泌使用强化的支架在体内使用功能。我们将确定将FGF7和FGF10纳入 L1P-FH（称为EP-FH）支架允许分泌功能保持完整的延长持续时间受照射的SMG小鼠模型。 AIM 3：将恢复体内辐照的SG的全部功能。我们将结合我们的带有聚合微粒的EP-FH支架，以释放临时的促血管生成和促染色GF 序列，模仿体内生理学，以增强辐射后SMG的功能恢复治疗。总而言之，我们提出的研究将使用L1P恢复SG功能，将我们的发现扩展到迄今为止。从而允许更大的可持续性和更深的功能。