Proximal Tubule Albumin Transport in Disease States

描述（由申请人提供）：虽然蛋白尿，特别是白蛋白尿的临床相关性已得到充分证明，但不同屏障成分对白蛋白尿的定量机制贡献或作用仍然是一个相当令人兴奋和争论的领域。最近几个实验室利用不同的科学方法的数据已经描绘了近端小管在白蛋白重吸收和回收中的潜在作用，作为白蛋白尿的尿屏障的另一个重要决定因素。因此，本申请提出在相同大鼠中以纵向方式解剖并量化在生理和疾病条件下肾小球和近端小管对蛋白尿的贡献。结构，功能和机制的观察将相互关联，以促进我们目前对这一临床重要现象的理解。我们的总体假设是，肾小球通透性和近端小管细胞发挥基本的、生理的、协同的、相互作用的和诱导的作用，以试图维持生理状态并最大限度地减少蛋白尿。我们进一步假设肾小球白蛋白通透性或近端小管白蛋白回收的急性或慢性改变可直接影响白蛋白尿。为了直接评估这一假设，我们已经开发了必要的技术，方法和动物模型，以解剖，量化，理解和相互关联的作用，急性和慢性变化的肾小球通透性和近端肾小管细胞重吸收和转胞吞过滤白蛋白。 公共卫生相关性：虽然尿中蛋白质（白蛋白）在疾病进展中的重要性是已知的，但介导白蛋白存在和毒性作用的关键机制仍有待确定。拟议的研究将导致对蛋白尿中涉及的细胞过程的机制理解增强，它们在导致蛋白尿的疾病过程中的作用，从而引领可能的新型治疗方法的发展。

DESCRIPTION (provided by applicant): While the clinical relevance of proteinuria, and especially albuminuria, has been well documented the quantitative mechanistic contribution or role of different barrier components to albuminuria remains an area of considerable excitement and debate. Recent data from several laboratories utilizing different scientific approaches have delineated a potential role of proximal tubules in albumin reabsorption and reclamation as another important determinant of the urinary barrier to albuminuria. Therefore, the present application proposes to dissect apart and quantify glomerular and proximal tubule contributions to albuminuria under physiologic and disease conditions in a longitudinal fashion in the same rats. Structural, functional and mechanistic observations will be interrelated to advance our present understanding of this clinically important phenomenon. Our Overall Hypothesis is that both glomerular permeability and proximal tubule cells play fundamental, physiologic, synergistic, interactive and inducible roles to try and maintain the physiological state and minimize albuminuria. We further hypothesize that acute or chronic alterations in glomerular albumin permeability or in proximal tubule albumin reclamation can directly affect albuminuria. To directly evaluate this hypothesis we have developed the necessary techniques, approaches and animal models to dissect, quantify, understand and interrelate the role of acute and chronic changes in glomerular permeability and proximal tubular cell reabsorption and transcytosis of filtered albumin. PUBLIC HEALTH RELEVANCE: While the importance of protein (albumin) in the urine in disease progression is known, the key mechanism(s) mediating the presence of and toxic effects of albumin still remain to be determined. The proposed studies will lead to an enhanced mechanistic understanding of the cellular processes involved in albuminuria, their role in disease processes resulting in proteinuria thereby leading the way toward development of possible novel therapeutic approaches.