Mechanisms of pituitary gonadotrope cell maintenance and renewal in adult mice

身体的器官，如大脑和心脏，是由专门的细胞类型组成的，这些细胞类型执行这些器官的必要功能。大多数器官中的大多数细胞都会死亡，并在一生中不断被替换。这些细胞包括睾丸中的精子细胞和肠道内的细胞。其他细胞，如大脑中的神经元或所谓的心脏心肌细胞，被认为会伴随个体的一生，即使在受损或死亡时也不会被取代。这就是为什么中风和心脏病等事件被认为对大脑和心脏产生不可逆转的影响，而其他器官（如骨骼和肌肉）在受伤后可以自我修复。身体的大多数器官在一生中都具有自我更新的能力，尽管更新的速度和方式各不相同。例如，一些器官具有通常被称为祖细胞或承诺干细胞的东西，它们有能力用构成它们的细胞类型重新填充给定器官，但缺乏在其他器官中重新填充细胞类型的能力。在其他器官中，一些细胞类型具有自我更新的能力。也就是说，它们分裂，复制自己。还有其他方法可以替换细胞。例如，一些组织由几种不同类型的细胞组成，这些细胞具有不同的功能。在某些条件下，一种细胞类型可以转化为另一种细胞类型。因此，身体已经进化出许多不同的机制来替换不同器官中的细胞。总的来说，这个过程被称为组织稳态，简单地反映了这样一个事实，即细胞在个体的一生中受损和死亡，需要被替换，以便个体在相对健康的状态下继续生存。可以说，衰老反映了随着个人年龄的增长，身体替换细胞的能力下降。脑下垂体是一个位于大脑底部的器官。它由五种主要的细胞类型组成，每一种都产生不同的激素，控制卵巢、睾丸、肾上腺、甲状腺、肝脏和乳房功能的不同方面。激素是在一个器官或组织中产生的化学信使，通过血液流动来调节其他器官或组织的活动。在生殖系统中，脑垂体中的一种叫做促性腺激素的细胞会产生两种激素，分别是促卵泡激素和促黄体激素。一旦从促性腺细胞释放到血液中，这两种激素就会进入卵巢和睾丸，在那里它们控制配子（卵子和精子）的发育以及类固醇激素（如睾酮和雌激素）的产生。虽然人类和其他哺乳动物在成年后的大部分时间里都有繁殖能力，但我们还不知道垂体的促性腺细胞是在胎儿发育的早期出生并伴随个体的一生（就像大脑和心脏细胞一样），还是在整个生命过程中死亡并被替换。如果它们被替换，我们不知道身体是如何完成这一壮举的。在目前的拨款申请中，我们建议使用转基因小鼠来回答这些以前未回答的问题。这项工作的结果将促进我们对脊椎动物生殖生理学最基本方面的理解。

The organs of the body, like the brain and heart, are made up of specialized cell types that perform the necessary functions of those organs. Most cells in most organs die and are replaced continuously throughout life. These include sperm cells in the testicles and the cells that line the intestines. Other cells, such as neurons in the brain or so-called cardiomyocytes of the heart, are thought to last the lifetime of the individual and are not replaced, even when damaged or dying. That is why, for example, events such as strokes and heart attacks are thought to produce irreversible effects on the brain and heart, whereas other organs (such as bones and muscles) can repair themselves following injury. Most organs of the body possess the ability to replace themselves throughout life, though do so at different rates and in different ways. For example, some organs have what are most commonly called progenitor or committed stem cells that have the ability to repopulate a given organ with the cell types that comprise them but that lack the ability to repopulate cell types in other organs. In other organs, some cell types have the ability to self-renew. That is, they divide, making copies of themselves. There are still other ways for cells to be replaced. For example, some tissues are comprised of several different cell types with different functions. Under some conditions, one cell type may transform into another cell type. Therefore, the body has evolved many different mechanisms for replacing cells in different organs. Collectively, this process is referred to as tissue homeostasis and simply reflects the fact that cells get damaged and die over the lifetime of the individual and need to be replaced for the individual to continue to survive in a relatively healthy state. Arguably, aging reflects the reduced ability of the body to replace cells as individuals age. The pituitary gland is an organ that sits at the base of the brain. It is comprised of five main cell types, each of which makes different hormones that control different aspects of ovarian, testicular, adrenal, thyroid, liver, and breast function. Hormones are chemical messengers made in one organ or tissue that travel through the bloodstream to regulate the activity of other organs or tissues. In the case of the reproductive system, a cell type in the pituitary gland called the gonadotrope makes two hormones called follicle-stimulating hormone and luteinizing hormone. Once released into the blood from the gonadotrope cell, these two hormones travel to the ovaries and testicles where they control the development of the gametes (eggs and sperm) as well as the production of steroid hormones such as testosterone and estrogen. Though humans and other mammals have the capacity to reproduce for much of their adult lives, we do not yet know whether the gonadotrope cells of the pituitary are born early in fetal development and last the lifetime of the individual (as with brain and heart cells) or whether they die and are replaced throughout life. If they are replaced, we do not know how the body accomplishes this feat. In the present grant application, we propose to use genetically modified mice to answer these previously unanswered questions. The results of this work will advance our understanding of one the most fundamental aspects of vertebrate reproductive physiology.