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.

项目总结/文摘