Functional Assembly of Salivary Cells to Relieve Xerostomia

唾液细胞的功能组装以缓解口干症

• 批准号: 8878217
• 负责人: MARY C FARACH-CARSON
• 金额: $ 60.18万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878217
• 关键词: Acinar Cell; Address; Adverse effects; Affect; Agonist; Animal Model; Artificial Saliva; Autologous; Basement membrane; Biocompatible; Biological; Biological Process; Blood Vessels; Body Weight decreased; Cell Communication; Cell Survival; Cells; Chemicals; Clinical; Collaborations; Complex; Cues; Deglutition; Dental; Dental caries; Differentiation and Growth; Disease Progression; Ductal Epithelial Cell; Eating; Engineering; Enzymes; Epithelial Cells; Epitopes; Ethylene Glycols; Extracellular Matrix; Extracellular Matrix Proteins; Gel; Gland; Goals; Growth Factor; Head and Neck Cancer; Head and neck structure; Health; Human; Hyaluronic Acid; Hybrids; Hydrogels; Immune response; Implant; In Vitro; Individual; Infection; Injury; Ion Channel; Laboratories; Mechanics; Membrane Proteins; Methods; Modeling; Modification; Morphogenesis; Myoepithelial cell; Natural regeneration; Operative Surgical Procedures; Oral cavity; Organ; Patients; Peptides; Performance; Phenotype; Physiological; Population; Prevention; Production; Property; Quality of life; Radiation; Radiation therapy; Radiation-Protective Agents; Rattus; Recovery; Regenerative Medicine; Research Personnel; Saliva; Salivary; Salivary Glands; Signal Transduction; Site; Solutions; Stem cells; Stimulus; Structure; Surgical Oncologist; System; Technology; Therapeutic; Tissue Engineering; Tissue Sample; Tissues; Transplantation; Xerostomia; angiogenesis; base; cell type; controlled release; copolymer; design; ethylene glycol; flexibility; functional restoration; human tissue; implantation; in vivo; in vivo Model; novel; particle; perlecan; physical property; progenitor; prototype; reconstitution; response; restoration; saliva secretion; salivary acinar cell; salivary cell; scaffold; tissue regeneration; water channel

DESCRIPTION (provided by applicant): Xerostomia, or 'dry mouth', is the inevitable consequence of the standard radiation treatment for head and neck cancers, and leads to severe dental issues (caries, infections, decay), difficulties in swallowing, speaking, and eating, gradual weight loss, and overall discomfort. Current therapies have not proven effective in long term application, and few tissue engineering strategies have been applied to this problem. In this application, we assemble three PIs with the necessary engineering, biological, and clinical expertise to address salivary regeneration using core biological design principles. In Aim 1, Xinqiao Jia's laboratory will develop hyaluronic acid (HA) gels as a modular cellular scaffolding material. HA is a compelling material for salivary gland regenerative medicine, as it is naturally derived, biodegradable, and offers flexible tuning of chemical and mechanical properties to match those of native tissue. Microscale HA hydrogel particles (HGP) will be used as growth factor depots to stimulate salivary cell organization, gland morphogenesis, and vascular input to the neotissue. In Aim 2, Cindy Farach-Carson's laboratory will apply these technologies in vitro, leveraging their ability to reliably isolate and expand acinar, ductal, and myoepithelial cells fro human tissue samples. Bioactive fragments will be incorporated into the HA matrix to facilitate acinar/ductal cell organization, and cell reconstitution will be conducted in a stepwise fashion to insure proper lumen formation, polarity, and function. In Aim 3, Robert Witt will conduct in vivo implantations of HA matrices in an animal model, to determine the host response to the HGP growth factors, the viability of the neo-salivary glands, and a functional assessment of saliva production, content, and quality. These three Aims combine fresh discoveries from an existing collaboration among the three PIs, and maintain a clear goal of eventual translational application.

描述（由申请人提供）：口干症或“口干”是头颈癌标准放射治疗的不可避免的结果，并导致严重的牙齿问题（龋齿、感染、腐烂）、吞咽、说话困难、和吃饭， 体重逐渐减轻，全身不适。目前的疗法尚未被证明在长期应用中有效，并且很少有组织工程策略应用于这个问题。在此应用中，我们汇集了三个具有必要的工程、生物学和临床专业知识的 PI，以利用核心生物学设计原理解决唾液再生问题。在目标 1 中，贾新桥的实验室将开发透明质酸 (HA) 凝胶作为模块化细胞支架材料。 HA 是一种引人注目的唾液腺再生医学材料，因为它是天然衍生的、可生物降解的，并且可以灵活调整化学和机械特性以匹配天然组织的特性。微型 HA 水凝胶颗粒 (HGP) 将用作生长因子库，以刺激唾液细胞组织、腺体形态发生和新组织的血管输入。在目标 2 中，Cindy Farach-Carson 的实验室将在体外应用这些技术，利用其从人体组织样本中可靠分离和扩增腺泡、导管和肌上皮细胞的能力。生物活性片段将被整合到HA基质中以促进腺泡/导管细胞组织，并且细胞重建将以逐步的方式进行 确保正确的管腔形成、极性和功能。在目标 3 中，Robert Witt 将在动物模型中进行 HA 基质的体内植入，以确定宿主对 HGP 生长因子的反应、新唾液腺的活力以及唾液产生、含量和唾液分泌的功能评估。质量。这三个目标结合了三个 PI 之间现有合作的新发现，并保持了最终转化应用的明确目标。

项目成果

An atlas of active enhancers across human cell types and tissues.

跨人类细胞类型和组织的活性增强子图谱。

• 发表时间: 2014-03-27
• 影响因子: 64.8
• 作者: Andersson, Robin;Gebhard, Claudia;Miguel;Hoof, Ilka;Bornholdt, Jette;Boyd, Mette;Chen, Yun;Zhao, Xiaobei;Schmidl, Christian;Suzuki, Takahiro;Ntini, Evgenia;Arner, Erik;Valen, Eivind;Li, Kang;Schwarzfischer, Lucia;Glatz, Dagm
• 通讯作者: Glatz, Dagm

Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D.

调整水凝胶特性以促进 3D 唾液腺球体的组装。

• 发表时间: 2016-12-12
• 影响因子: 5.8
• 作者: Ozdemir, Tugba;Fowler, Eric W;Liu, Shuang;Harrington, Daniel A;Witt, Robert L;Farach;Pradhan;Jia, Xinqiao
• 通讯作者: Jia, Xinqiao

Primary Salivary Human Stem/Progenitor Cells Undergo Microenvironment-Driven Acinar-Like Differentiation in Hyaluronate Hydrogel Culture.

原代唾液人类干/祖细胞在透明质酸水凝胶培养中经历微环境驱动的腺泡样分化。

• 发表时间: 2017-01
• 影响因子: 6
• 作者: Srinivasan, Padma Pradeepa;Patel, Vaishali N;Liu, Shuang;Harrington, Daniel A;Hoffman, Matthew P;Jia, Xinqiao;Witt, Robert L;Farach;Pradhan
• 通讯作者: Pradhan

Dynamic Assembly of Human Salivary Stem/Progenitor Microstructures Requires Coordinated α1β1 Integrin-Mediated Motility.

人类唾液干/祖微结构的动态组装需要协调的α1β1 整合素介导的运动。

• 发表时间: 2019
• 作者: Wu, Danielle;Witt, Robert L;Harrington, Daniel A;Farach
• 通讯作者: Farach

Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function.

用于评估肌上皮细胞功能的唾液腺微组织的自下而上组装。

• DOI: 10.1016/j.biomaterials.2017.07.022
• 发表时间: 2017-10
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Ozdemir T;Srinivasan PP;Zakheim DR;Harrington DA;Witt RL;Farach-Carson MC;Jia X;Pradhan-Bhatt S
• 通讯作者: Pradhan-Bhatt S