Functional characterizations of the Sdx1 domain during cloacal septation

描述（由申请人提供）：我们的研究重点是泄殖腔分隔的潜在机制。推测的尿直肠隔沿着背腹轴将泄殖腔分开。背侧隔室形成直肠和肛门，腹侧尿生殖窦形成膀胱和尿道。泄殖腔分隔也与外生殖器的形成有关 因此，泄殖腔分隔缺陷几乎总是伴随生殖器结节异常。关于泄殖腔分隔的主要问题，如胚胎起源和尿直肠隔的分子决定因素，仍然知之甚少。这些都是重要的问题，因为缺乏基础知识是理解先天性泌尿生殖道出生缺陷病因的主要障碍，先天性泌尿生殖道出生缺陷是人类最常见的疾病之一。 尽管现有的各种模型和解释，我们的泄殖腔形态发生和发病机制的基本理解仍然非常有限。我们的近期目标是了解泄殖腔分隔的分子和细胞基础，最终目标是应用这些基础知识来帮助减少与泌尿直肠相关的疾病。根据我们发表的初步研究结果，我们假设Sdx 1结构域是泄殖腔分隔和泌尿生殖系统发育所必需的。表达Sdx 1的间充质细胞和谱系受到限制，并且不对称地定位在发育中的泄殖腔旁边。据我们所知，这是第一次，一个分子定义的离散域已被确定，并牵连在泄殖腔形态发生。我们认为，这一假设是创新的，因为它代表了对现有模型的实质性偏离。为了确定Sdx 1结构域的功能意义，我们设计了三个互补的目标：功能特征的Sdx 1结构域;以确定Dkk 1是否抑制Sdx 1结构域的形成;并确定内胚层Shh信号是否诱导Sdx 1结构域的形成。预期的贡献，拟议的研究是我们的泄殖腔分隔过程的细胞和分子机制的基本理解的进步。这一贡献将对发育生物学和人类先天性泌尿直肠疾病领域产生重要的积极影响。Sdx 1结构域的遗传和环境调节因子的未来研究将很可能导致更好地理解先天性泌尿直肠疾病的潜在机制和新的靶向和/或预防策略。 公共卫生相关性：这项建议与公共卫生有关，因为了解下尿路的基本发育生物学是更好地了解先天性泌尿生殖道出生缺陷的病因和开发新的预防策略的许多步骤中的第一步，先天性泌尿生殖道出生缺陷是人类最常见的先天性泌尿生殖道出生缺陷之一。拟议的研究是相关的NIH的使命的一部分，在追求基础知识，以延长健康的生活，减少疾病和残疾的负担。

DESCRIPTION (provided by applicant): Our research focuses on the underlying mechanism of cloacal septation. The putative urorectal septum divides the cloaca along dorsoventral axis. The dorsal compartment forms the rectum and anus, and the ventral urogenital sinus gives rise to the bladder and urethra. Cloacal septation is also linked with formation of the external genital tubercle and urethral tube; as a result, cloacal septation defects are almost always coupled with genital tubercle anomalies. Principle questions regarding cloacal septation, such as the embryonic origin and molecular determinants of the urorectal septum, remain poorly understood. These are important questions because lack of the fundamental knowledge is a major barrier to understanding the etiology of congenital urogenital birth defects, which are among the most common in humans. In spite of various existing models and interpretations, our fundamental understanding of cloacal morphogenesis and pathogenesis remains very limited. Our immediate objective is to understand the molecular and cellular basis of cloacal septation with an ultimate goal of applying this basic knowledge to help reduce urorectal-related diseases. Based on our published and preliminary findings, we have hypothesized that the Sdx1 domain is required for cloacal septation and urogenital development. The Sdx1- expressing mesenchymal cells and lineages are restricted and asymmetrically localized next to the developing cloaca. To our knowledge, this is the first time that a molecularly defined discrete domain has been identified and implicated in cloacal morphogenesis. In our opinion, this hypothesis is innovative because it represents a substantial departure from existing models. To determine the functional significance of the Sdx1 domain, we have designed three complementary aims: to functionally characterize the Sdx1 domain; to determine if Dkk1 inhibits formation of the Sdx1 domain; and to determine if endodermal Shh signal induces formation of the Sdx1 domain. The expected contribution of the proposed research is the advancement of our basic understanding of cellular and molecular mechanisms underlying the cloacal septation process. This contribution would have an important positive impact on fields of developmental biology and human congenital urorectal diseases. Future studies of genetic and environmental regulators of the Sdx1 domain would most likely lead to a better understanding of the underlying mechanism(s) and novel targeting and/or preventative strategies for congenital urorectal disease. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health because understanding basic developmental biology of lower urinary tract is the first of many steps towards a better understanding of etiology of and development of novel preventative strategies of congenital urogenital birth defects, which are among the most common in humans. The proposed research is relevant to the part of NIH's mission in pursuing fundamental knowledge to extend healthy life and to reduce the burdens of illness and disability.