Project 1 - Cardiovascular and Regenerative Medicine

项目1-心血管和再生医学

• 批准号: 8663294
• 负责人: TABASSUM AHSAN
• 金额: $ 30.32万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8663294
• 关键词: 3-Dimensional; Activities of Daily Living; Affect; Age; Aging; Anatomy; Animal Experimentation; Animals; Autologous; Autologous Bone Marrow Transplantation; Binding; Biochemical; Biological; Biological Models; Blocking Antibodies; Bone Marrow; Caliber; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Communication; Cell Proliferation; Cell Transplantation; Cell physiology; Cells; Clinical Research; Clinical Trials; Coculture Techniques; Communication; Complex; Control Animal; Cues; Dependency; Endothelial Cells; Environment; Event; Gene Expression; Gene Silencing; Goals; Heart; Human; Hydrostatic Pressure; Immigration; Instruction; Length; Liquid substance; Mechanics; Mediating; Mentors; Mesenchymal Stem Cells; Modeling; Molecular; Muscle Contraction; Myocardial; Myocardial Infarction; Myocardium; Notch Signaling Pathway; Outcome; Patients; Phenotype; Process; Property; Publishing; Regenerative Medicine; Reperfusion Therapy; Research; Role; Smooth Muscle Myocytes; Source; Stem cell transplant; Stem cells; Stimulus; Structure; System; Testing; Therapeutic; Tissue Engineering; Tissues; Vascular Endothelial Growth Factors; adult stem cell; age effect; age related; angiogenesis; improved; in vitro Model; juvenile animal; migration; regenerative; response; shear stress; tissue regeneration; tissue repair; two-dimensional

One potential treatment for damaged cardiac tissue post myocardial infarction is the transplantation of autologous bone marrow-derived mesenchymal stem cells (MSCs) to stimulate angiogenesis, resulting in reperfusion of ischemic tissue that enables subsequent tissue regeneration. An inherent challenge for this approach is patient age, and thus cell donor age, which may result in decreased number and functionality of available stem cells. The objective of this proposal is to determine the effect of donor age on M8Cdependent angiogenesis for ischemic cardiac tissue. Donor ages of MSCs will be categorized as 30's, 40's, 50's, and 60's. The hypothesis is that increased donor age inhibits MSC-dependent angiogenesis within the challenging cellular and mechanical environment of the myocardium. To test this hypothesis, this proposal will utilize a differential approach of tissue engineering systems that progressively increases the complexity of the in vitro models to include, separately and in combination, heterotypic human cell phenotypes, soluble factor communication, direct cell-cell contact, 3D environments, and applied cyclic strain. Specific Aim 1 is to determine the effect of MSC donor age on endothelial cell (EC) processes and smooth muscle cell-like functions for angiogenesis in an indirect co-culture model. The hypothesis is that increased donor age mitigates MSC-dependent increases in EC proliferation, migration, and assembly through decreased secretion of VEGF. Antibody blocking and gene silencing will be used to focus on the mechanisms dependent on VEGF. Aim 2 is to determine the effect of MSC donor age on vessel-like structure formation within a cardio-relevant mechanical environment using a direct co-culture model. The hypothesis is that increased donor age mitigates MSC-dependent vessel stabilization and formation through decreased interaction with ECs via the notch signaling pathway. We will utilize 2- and 3-dimensional direct co-culture models and applied cyclic strain to assess the length, diameter, complexity, and stability of vessels formed. Gene silencing will be used to focus on the JAGGED1-N0TCH3 interactions between ECs and MSCs during direct cell-cell communication as the mechanism of vessel stabilization.

心肌梗死后受损心脏组织的一种潜在治疗方法是移植 自体骨髓间充质干细胞（MSC）刺激血管生成，导致 缺血组织的再灌注使得随后的组织再生成为可能。这是一个固有的挑战 方法是患者年龄，因此细胞供体年龄，这可能导致减少的数量和功能， 可用的干细胞。本提案的目的是确定供体年龄对M8 C依赖性 缺血性心脏组织的血管生成。骨髓间充质干细胞的供体年龄将被分类为30岁，40岁， 50年代和60年代。假设供体年龄的增加抑制了MSC依赖的血管生成， 挑战心肌的细胞和机械环境。为了验证这一假设， 将利用组织工程系统的差异化方法， 包括，单独和组合，异型人类细胞表型，可溶性 因子通信、直接细胞-细胞接触、3D环境和施加的循环应变。具体目标1是 确定MSC供体年龄对内皮细胞（EC）过程和平滑肌细胞样增殖的影响， 在间接共培养模型中的血管生成功能。假设捐献者年龄的增加 通过降低内皮细胞的增殖、迁移和组装， VEGF的分泌。抗体阻断和基因沉默将被用来关注的机制 依赖于VEGF。目的2是确定MSC供体年龄对血管样结构形成的影响 在心脏相关的机械环境中使用直接共培养模型。前提是 供体年龄的增加通过降低 通过notch信号通路与EC相互作用。我们将利用二维和三维直接共培养 模型和应用循环应变来评估形成的血管的长度、直径、复杂性和稳定性。 基因沉默将用于关注在细胞凋亡过程中EC和MSC之间的JAGGED 1-N 0 TCH 3相互作用。 直接细胞间通讯作为血管稳定的机制。