ENDOCRINE REGULATION OF GERM CELL APOPTOSIS IN THE MALE

男性生殖细胞凋亡的内分泌调节

• 批准号: 6637963
• 负责人: AMIYA P SINHA HIKIM
• 金额: $ 29.08万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-06 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637963
• 关键词: BCL2 gene /protein; CD95 molecule; apoptosis; confocal scanning microscopy; cysteine endopeptidases; cytochrome c; enzyme induction /repression; enzyme inhibitors; follicle stimulating hormone; gene mutation; gonadotropins; hormone regulation /control mechanism; immunoelectron microscopy; immunofluorescence technique; laboratory mouse; laboratory rat; luteinizing hormone; male; p53 gene /protein; sperm; spermatogenesis; testosterone

DESCRIPTION: (Scanned from the applicant's abstract) Recent studies have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis, and can be triggered by various physiological and pathological stimuli. The mechanisms by which these proapoptotic stimuli activate germ cell apoptosis are not well understood. The principal intracellular effectors of apoptosis are a family of cysteine proteases called caspases. These enzymes participate in a cascade involving initiator and executioner caspases that is triggered in response to proapoptotic signals. Active executioner caspases are then involved in the cleavage of key cellular proteins, resulting in eventual cell death. Four specific aims are proposed. Specific Aim 1 will focus on the characterization of the key molecular components of the intrinsic and extrinsic death pathways leading to caspase activation and increased germ cell apoptosis triggered by deprivation of the gonadotropic support or by mildly increased scrotal temperature. In Specific Aim 2, we will determine whether inhibition of germ cell apoptosis by replacement therapy of human FSH and/or LH, in the hormone deprivation model, will reverse the apoptosis related changes in the gene expression. Specific Aim 3 of this proposal will address the role of in vivo pre-treatments of rats with a broad-spectrum caspase inhibitor or a selective inhibitor of caspase 3 like proteases in preventing or attenuating the increased germ cell apoptosis induced by the hormonal and non-hormonal regulatory stimuli. Specific Aim 4 will focus on further characterization of the role of some of the key upstream modulators (p53, Bcl-2, Fas, and Fas L) of caspase activation in directing germ cell fate using mice harboring null mutation of either p53 or Bcl-2, or mice lacking functional Fas (lpr[cg]) or Fas L (gld). Results of these studies will provide insight into the basic control mechanisms of spermatogenesis in normal and pathological states and will be applicable to the assessment and management of male factor infertility as well as more targeted approaches to male contraception.

描述：（从申请人的摘要中扫描）最近的研究 证明凋亡是生殖细胞死亡的基本机制 在正常的精子发生期间，可以通过各种生理触发 和病理刺激。这些促凋亡刺激的机制 激活生殖细胞凋亡尚不清楚。校长 细胞凋亡的细胞内效应因子是一个称为半胱氨酸蛋白酶的家族 caspase。这些酶参与涉及发起人的级联和 响应促凋亡信号触发的execution子手caspase。 然后，主动executioner caspase参与了钥匙蜂窝的裂解 蛋白质，最终导​​致细胞死亡。提出了四个具体目标。 特定的目标1将集中于关键分子的表征 固有和外在死亡途径的组成部分导致caspase 因剥夺而触发的激活和增加的生殖细胞凋亡 促性腺激素支撑或通过轻度升高阴囊温度。具体 AIM 2，我们将确定是否抑制生殖细胞凋亡 在激素剥夺模型中，人类FSH和/或LH的替代疗法， 将扭转基因表达中凋亡相关的变化。具体目标 该提案的3个将解决大鼠体内预处理的作用 广谱caspase抑制剂或caspase 3的选择性抑制剂 预防或衰减生殖细胞凋亡增加的蛋白酶 由激素和非荷尔蒙调节刺激诱导。具体目标4 将集中于进一步表征上游一些关键的角色 指导胚芽的调节剂（p53，bcl-2，fas和fas l） 使用带有p53或Bcl-2的无效突变的小鼠或小鼠的细胞命运 缺乏功能性FA（LPR [CG]）或FAS L（GLD）。这些研究的结果将 提供对正常生理发生的基本控制机制的见解 和病理状态，将适用于评估和管理 男性因素不育以及男性的更具针对性的方法 避孕。