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.

抽象的据美国癌症协会称，今年将有超过 60,000 人患上头颈癌年，这些患者必须接受放射治疗才能生存。这种治疗会定期破坏唾液腺体（SG），导致分泌功能丧失，这通常是永久性的。目前的治疗方法仍然有效基本上无效，治疗干预仅限于使用唾液替代品，效果适中效果和药物只能提供暂时的缓解。鉴于需求的高度和由于当前疗法的局限性，开发替代疗法来恢复 SG 功能至关重要。在为了应对上述挑战，我们建议引入FGF7和FGF10，两者都能激活 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）。强化我们的支架以增强 SG 形态发生和分化后，我们将尽管如此，仍然面临着脉管系统和神经系统缺失或发育不良的问题，如重复研究表明，受辐射的 SG 血管化和神经支配丧失。针对这些为了应对挑战，我们将借鉴之前的发现，表明 VEGF 和 FGF9 有助于血管形成和神经营养因子（例如 NGF）促进神经支配（目标 3）。我们假设改良的 FH 支架含有固定化L1肽（L1p）和GF（L1p-GF-FH）将促进功能组织的形成辐照SG。目标 1：将使用体外强化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）支架中是否允许分泌在受辐射的 SG 中长时间保持完整的功能。目标 2：将表现出持续的分泌使用强化支架在体内发挥功能。我们将确定是否将 FGF7 和 FGF10 纳入 L1p-FH（称为 Ep-FH）支架允许分泌功能在较长时间内保持完整。受辐射的 SMG 小鼠模型。目标3：恢复体内受辐射SG的全部功能。我们将结合我们的具有聚合物微粒的 Ep-FH 支架可在时间上释放促血管生成和促神经支配 GF 序列，模仿体内生理学，以增强放射后 SMG 的功能恢复治疗。总之，我们提出的研究将扩展我们迄今为止的发现，使用 L1p 恢复 SG 功能，从而实现更大的可持续性和更深层次的功能。