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Molecular Mechanisms of Leydig Cell Regeneration

间质细胞再生的分子机制

基本信息

批准号：
10673087
负责人：
Jasmin LaKia Jeffery
金额：
$ 4.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673087
关键词：
Ablation Adult Age Aging Alkanesulfonates Androgens Automobile Driving Biology Candidate Disease Gene Cell Cycle Cell Death Cell Proliferation Cell Separation Cells Characteristics Chemicals Cre driver Cytotoxic agent Data Development Ethane Gene Expression Profile Gene Expression Profiling Genes Genetic Germ Cells Goals Growth In Vitro Injury Interphase Cell Male Infertility Malignant Neoplasms Modeling Molecular Monitor Mus Natural regeneration Organ Organism Pathway interactions Personal Satisfaction Physiological Population Process Rattus Regenerative research Role Signal Pathway Signal Transduction Somatic Cell Source Supporting Cell System Testing Testis Tissue Model Tissues Work candidate marker candidate selection cell regeneration cell type differential expression extracellular improved in vivo regeneration inhibitor injured interest leydig interstitial cell male male fertility male health men mouse genetics novel pharmacologic precursor cell progenitor regeneration model regenerative regenerative cell repaired response response to injury self-renewal single-cell RNA sequencing small molecule sperm cell stem cells tissue regeneration tool transcriptome transcriptomics

项目摘要

Cells lost to normal wear and tear in many adult tissues are replaced with the activity of stem cells. In response to injury, however, cells can use entirely different strategies to repair and regenerate tissues. Injured tissues can be regenerated through the activation of stem cells or from progenitor cells that, unlike stem cells, are incapable of asymmetric division and self-renewal. The dramatic cellular changes that occur during regeneration are thought to arise from altered signaling in the tissue microenvironment, or niche, but the mechanisms regulating regeneration are largely unknown. A classical model of regeneration after injury is the adult rat testis. In the testis, somatic cells create a microenvironment that contributes to the germ cell niche. Critical somatic support cells include Leydig cells, the major androgen producing cells in males, which are required for male health and fertility. Although Leydig cells are a quiescent cell type, and not thought to divide under normal conditions, they are chemically ablated by ethane dimethane sulfonate (EDS). Several weeks after chemical ablation, new Leydig cells repopulate the testis. The mechanism of Leydig cell regeneration and the progenitors from which they arise remain poorly understood, partially due to the lack of genetic tools available in rats. In vitro work has hinted at candidate markers that may identify progenitors of Leydig cell regeneration. The goal of this project is to determine the cellular mechanism and molecular mechanism of Leydig cell regeneration. Mouse genetics make it possible to interrogate the cellular mechanism of regeneration by use of an inducible genetic lineage tracing system. In preliminary data, a subset of somatic testis interstitial cells trace into new Leydig cells after ablation in mice. We will continue using this model to determine the both identity of the progenitor cells and whether this cell type is self-renewing. We will also determine the molecular mechanisms driving regeneration with the use of sc-RNA sequencing before, during, and after regeneration. Candidate genes implicated in signaling and Leydig cell development that are differentially expressed in regenerating cells will be tested for functional roles during regeneration using small molecule pathway inhibitors and available genetic tools. While small molecules are an accessible way to gain crude information about whether a signaling pathway is involved, sc-RNA sequencing will illuminate exactly which cells produce signals that initiate the progenitor response. Determining the cellular and molecular mechanisms of Leydig cell regeneration will significantly contribute to the understanding of adult tissue regeneration in vivo with broader implications for male fertility and health.

在许多成人组织中，由于正常磨损而失去的细胞被具有活性的干细胞所取代。在回应