Cell Fate Determination in Fetal Testes

胎儿睾丸细胞命运的测定

基本信息

批准号：
7735462
负责人：
Paul S. Cooke
金额：
$ 37.4万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7735462
关键词：
Adrenal Glands Adult Affect Androgens Biological Biology Birth Cell Count Cell Differentiation process Cell Lineage Cell Separation Cells Characteristics Congenital Abnormality Curiosities Defect Development Disease Embryonic Development Enzymes Erinaceidae Exhibits Fertility Funding Genetic Genetic Models Goals Gonadal structure Hormones In Vitro Instruction Label Life Ligands Luteinizing Hormone Modeling Molecular Newborn Infant Organ Parents Pathway interactions Population Postdoctoral Fellow Process SF1 Sexual Development Side Signal Pathway Somatic Cell Somatomedins Spermatogenesis Staging Testing Testis TimeLine Tissues Transplantation Undifferentiated base cell type clinically relevant fetal in vivo insight interest interstitial interstitial cell leydig interstitial cell loss of function male parent grant precursor cell programs reproductive research study sex sex development disorder smoothened signaling pathway stem stem cell population tissue regeneration transcription factor

项目摘要

A central interest in developmental, reproductive, and stem biology is how common precursor cells acquire instruction to differentiate into specialized cell types in various organs. Understanding how cell fates are determined not only satisfies the curiosity on how tissues form, but also has a great implication in controlling and manipulating the differentiation program for tissue regeneration and therapeutical purposes. The main goal of this proposal is to understand how fetal and adult Leydig cell lineages, the cell types responsible for masculinization and fertility of the male, are established. Fetal and adult Leydig celis are two distinct androgen-producing celis that appear at different developmental stages and exhibit unique morphological and molecular characteristics. Defects in the establishment of fetal and adult Leydig cell populations or their ability to produce hormones have a profound impact on differentiation of male reproductive tract, spermatogenesis, and fertility. It is therefore essential to understand how these two Leydig celi populations arise and their differentiation is regulated. Our preliminary results suggest that fetal and adult Leydig cells originate from a common precursor in fetal life and the hedgehog (Hh) signaling pathway is responsible for the separation of these two Leydig celi lineages from the common precursor population. We therefore propose to 1) investigate the effects of ectopic activation of the Hh in the differentiation of fetal and adult Leydig cells, 2) isolate the putative Leydig cell precursors and examine their ability to differentiate into adult Leydig cells, and 3) examine the contribution of Gli1-positive interstitial cells to adult Leydig cells. This application will not only provide an insight into the biological basis of cell fate determination in testes, but will also have clinical relevance by identifying processes susceptible to disorders of male sexual development.

对发育，生殖和STEM生物学的核心兴趣是很普遍的前体细胞获取指令，以分化各种专用细胞类型器官。了解如何确定细胞命运不仅满足对组织如何形成，但也对控制和操纵具有很大的意义组织再生和治疗目的的分化计划。主该提议的目标是了解胎儿和成人Leydig细胞谱系如何负责男性化和男性生育能力的细胞类型是已确立的。胎儿和成人leydig celis是两个不同的产生雄激素的celis 出现在不同的发育阶段，表现出独特的形态和分子特征。胎儿和成人Leydig细胞的缺陷种群或产生激素的能力对男性生殖道，精子发生和生育能力的分化。因此是了解这两个Leydig Celi人群如何出现及其分化受到调节。我们的初步结果表明胎儿和成人Leydig 细胞起源于胎儿生命和刺猬（HH）信号的共同前体途径负责将这两个Leydig Celi血统与共同的前体人口。因此，我们建议1）研究 HH在分化胎儿和成年Leydig细胞中的异位激活，2）分离株推定的leydig细胞前体，并检查它们分化为成人的能力 Leydig细胞和3）检查Gli1阳性间质细胞对成年的贡献 leydig细胞。该应用不仅将提供对生物学基础的见解睾丸中的细胞命运确定，但也将通过识别来具有临床相关性易受男性性发展疾病的过程。