Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function

对细胞外邻域进行逆向工程以支持功能组织单位：恢复卵巢功能的用例

• 批准号: 10689815
• 负责人: Monica M Laronda
• 金额: $ 40.2万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689815
• 关键词: 3-Dimensional; 5 year old; Address; Adolescent; Adult; Affect; Age; Anatomy; Atlases; Atomic Force Microscopy; Biochemical; Biological; Biopsy; Cardiovascular Diseases; Cell physiology; Cells; Childhood; Cognition Disorders; Collaborations; Cues; Cytoplasm; Data; Data Set; Development; Dimensions; Disease; ECM receptor; Engineering; Environment; Extracellular Matrix; Fertility; Future; Genetic Transcription; Germ Cells; Goals; Growth; Histologic; Hormone replacement therapy; Hormones; Human; Human BioMolecular Atlas Program; Image; Imaging technology; Individual; Life Expectancy; Longevity; Maps; Metastatic Malignant Neoplasm to the Ovary; Methods; Michigan; Modality; Modeling; Molecular Profiling; Multimodal Imaging; Multiomic Data; Neighborhoods; Nutrient; Oocytes; Ooplasm; Output; Ovarian; Ovarian Follicle; Ovarian hormone; Ovarian tissue cryopreservation; Ovary; Patients; Pennsylvania; Physicians; Population; Positioning Attribute; Process; Production; Progressive Disease; Proteins; Proteomics; Protocols documentation; Puberty; Publishing; Quality of life; Readability; Regenerative Medicine; Resources; Reverse engineering; Safety; Somatic Cell; Stromal Cells; Technology; Three-Dimensional Imaging; Tissue Engineering; Tissue atlas; Tissues; Translating; Universities; Woman; analysis pipeline; biocomputing; body system; cell type; comorbidity; egg; extracellular; fertility improvement; folliculogenesis; granulosa cell; imaging facilities; improved; induced pluripotent stem cell; insight; interstitial; interstitial cell; multiple omics; oocyte maturation; oocyte quality; pediatric patients; prepuberty; primary ovarian insufficiency; puberty transition; receptor binding; reconstruction; regenerative; regenerative therapy; response; restoration; scaffold; single-cell RNA sequencing; technology validation; tissue mapping; tool

PROJECT SUMMARY/ABSTRACT Static human biomolecular atlases miss dimensionality that is critical for establishing the healthy condition. We are uniquely positioned with rare resources and expertise to fill in these dimensions and enhance the healthy human ovary HuBMAP data. Here, we will contribute the developmental dimension by defining the change in interstitial cells across the pubertal transition; we will create the spatial dimension by probing the biochemical and physical cues of the extracellular matrix (ECM) across anatomical compartments and functional cell unit neighborhoods, and we will create the temporal dimension by investigating the changes in functional cell units during ooplasm maturation and hormone production. Without these added dimensions, the HuBMAP datasets are less effective in identifying and understanding disease modalities. Our long-term goal is to increase the utility of the ovary atlas using existing and new datasets to inform regenerative medicine technologies that improve the safety, efficacy and longevity of fertility and hormone restoration options for patients with premature ovarian insufficiency (POI), a disease that occurs in approximately 1% of women in the USA. Individuals with POI have a reduced quality of life and life expectancy of ~ 2 years shorter from comorbidities that include cognitive and cardiovascular diseases. We will incorporate data from the University of Pennsylvania (UPENN) HuBMAP Tissue Mapping Center (TMC) and the University of Michigan (UM) Chan Zuckerberg Initiative Human Cell Atlas (HCA) multiome maps of healthy adult ovaries. The Vanderbilt University Biomolecular Multimodal Imaging Center (BIOMIC) developed imaging and biocomputational analysis pipelines that enable 3D multimodel reconstruction and molecular profiling. Additionally, we have generated ECM and associated protein maps on model and human ovaries, in collaboration with the Northwestern University (NU) HuBMAP Rapid Technology Implementation (RTI) center. Finally, we have developed engineering tools, such as scaffolds that support ovarian follicles and protocols to make ovarian hormone-producing cells from human induced pluripotent stem cells (iPSCs). These resources and collaborations will provide valuable tissue and functional unit insights and, combined with our expertise in tissue engineering, will enable us to reverse engineer the extracellular neighborhood that supports ovarian follicle growth to improve fertility and hormone restoration options. We will (1) add developmental and spatial dimensions to the human ovary atlas to identify changes in the neighborhood that impact folliculogenesis, (2) demonstrate the utility of the HuBMAP data and tools to address important biological questions within the ovary and reverse engineer a neighborhood that supports follicle growth, and (3) reverse engineer a personalized ovarian hormone-replacement therapy from human iPSCs by defining and validating the response of cells to ECM environments. By achieving these milestones, we will add to the functionality of the HuBMAP ovary atlas, demonstrate the utility of these datasets, and develop pipelines and technologies for future regenerative technologies that may be developed from other HuBMAP tissue atlases.

项目概要/摘要 静态的人类生物分子图谱忽略了对于建立健康状况至关重要的维度。我们 拥有独特的优势，拥有稀有的资源和专业知识来填补这些维度并增强健康 人类卵巢HuBMAP数据。在这里，我们将通过定义变化来贡献发展维度 跨越青春期过渡的间质细胞；我们将通过探测生化来创造空间维度 跨解剖区室和功能细胞单位的细胞外基质 (ECM) 和物理线索 邻域，我们将通过研究功能细胞单元的变化来创建时间维度 在卵质成熟和激素产生期间。如果没有这些添加的维度，HuBMAP 数据集 在识别和理解疾病模式方面效果较差。我们的长期目标是提高效用 使用现有和新的数据集绘制卵巢图谱，为再生医学技术提供信息，从而改善 卵巢早衰患者的生育能力和激素恢复选择的安全性、有效性和寿命 功能不足 (POI)，这种疾病在美国大约 1% 的女性中发生。有 POI 的个人有 由于包括认知和认知障碍在内的合并症，生活质量下降，预期寿命缩短约 2 年 心血管疾病。我们将合并来自宾夕法尼亚大学 (UPENN) HuBMAP Tissue 的数据 制图中心 (TMC) 和密歇根大学 (UM) 陈·扎克伯格计划人类细胞图谱 (HCA) 健康成人卵巢的多组图。范德比尔特大学生物分子多模态成像中心 (BIOMIC) 开发了可实现 3D 多模型重建的成像和生物计算分析管道 和分子谱分析。此外，我们还在模型和人体上生成了 ECM 和相关蛋白质图谱 卵巢，与西北大学 (NU) HuBMAP 快速技术实施 (RTI) 合作 中心。最后，我们开发了工程工具，例如支持卵泡的支架和 从人类诱导多能干细胞（iPSC）中制造卵巢激素产生细胞的方案。这些 资源和合作将提供有价值的组织和功能单位见解，并结合我们的 组织工程方面的专业知识将使我们能够对支持细胞外的邻域进行逆向工程 卵泡生长是改善生育能力和激素恢复的选择。我们将 (1) 添加发展和 人类卵巢图谱的空间维度，以确定影响卵泡发生的邻近变化， (2) 展示 HuBMAP 数据和工具在解决重要生物学问题方面的效用 对卵巢和支持卵泡生长的邻域进行逆向工程，以及 (3) 对个性化的逆向工程进行逆向工程 通过定义和验证细胞对人类 iPSC 的反应进行卵巢激素替代疗法 ECM 环境。通过实现这些里程碑，我们将添加 HuBMAP 卵巢图谱的功能， 展示这些数据集的实用性，并开发未来再生的管道和技术 可以从其他 HuBMAP 组织图谱开发的技术。