CDF-1 REGULATION OF ZINC HOMEOSTASIS

描述（由申请人提供）：锌是一种重要的营养素，深刻影响人类健康，因为锌缺乏和锌过量都会导致广泛的病理学。锌在生物系统中起着许多作用，因为锌对许多蛋白质的功能是必需的，并且锌调节信号转导途径。详细了解锌代谢和体内平衡对于开发操纵锌以促进人类健康的新方法至关重要。目前对动物锌代谢的理解存在重大差距，因为用于吸收、分布、感觉和排泄锌的基本机制还不清楚。我们的长期目标是了解锌转运蛋白和结合蛋白网络如何以协调的方式调节动物的锌代谢。这一目标将通过分析锌进口商，锌出口商和新的基因参与锌代谢哺乳动物细胞和遗传上易处理的模式生物C。优雅了解蛋白质网络如何控制动物的锌代谢是医学研究的一个重要目标，因为这些信息可能会导致锌代谢异常引起的疾病的新治疗方法。 我们的初步结果建立了强大的C。elegans模型系统，用于通过开发允许操纵膳食锌的培养条件来研究锌代谢，创建测量锌代谢的测定法，以及鉴定影响锌代谢的新基因中的突变。这些结果支持了三个创新假设。(1)CDF-2通过将锌转运到溶酶体相关细胞器的内腔中，在锌的储存和解毒中起关键作用。(2)溶酶体相关的细胞器采取双叶的形态，以响应高锌条件，并提供锌的来源，在缺乏时动员。(3)组氨酸解氨酶在锌代谢中起重要作用，高水平的组氨酸促进锌的解毒。为了验证这些假设，我们提出了两个具体目标。目的1：明确CDF-2和溶酶体相关细胞器在锌储存中的作用。阐明CDF，ZIP和ferroportin等网络蛋白如何以协调的方式调节锌的储存和动员。目的2：探讨组氨酸解氨酶和组氨酸在哺乳动物细胞锌代谢中的作用。鉴定和表征介导C.和哺乳动物。这些实验建立在我们在前一个资助期内所取得的成就的基础上。elegans模型系统用于锌代谢的研究。这项提议将把这些发现扩展到脊椎动物系统，并利用C。elegans来阐明基因网络如何调节多细胞动物中锌的储存和动员。几种流行的人类疾病，如阿尔茨海默病，中风和癌症已与锌代谢异常，这些研究的结果可能会提出新的治疗策略，以解决锌毒性疾病。 公共卫生相关性：锌是一种对人体健康至关重要的必需营养素，因为锌缺乏和过量都会引起广泛的健康问题。这项研究将确定动物如何保护自己免受过量锌的影响，以及在过量时储存的锌如何在缺乏时使用。这些研究将为治疗锌过量或缺乏引起的疾病提出新的策略。

DESCRIPTION (provided by applicant): Zinc is an essential nutrient that profoundly affects human health, as zinc deficiency and zinc excess both result in a broad spectrum of pathologies. Zinc plays many roles in biological systems, since zinc is essential for the function of many proteins and zinc modulates signal transduction pathways. A detailed understanding of zinc metabolism and homeostasis is critical for the development of new approaches for manipulating zinc to promote human health. There are major gaps in the current understanding of zinc metabolism in animals, since fundamental mechanisms used to take up, distribute, sense and excrete zinc are not well understood. Our long-term goal is to understand how a network of zinc transporters and binding proteins act in a coordinated fashion to regulate zinc metabolism in animals. This goal will be addressed by analyzing zinc importers, zinc exporters and new genes involved in zinc metabolism using mammalian cells and the genetically tractable model organism C. elegans. Understanding how a network of proteins controls zinc metabolism in an animal is an important objective of medical research, since the information may lead to new therapeutic approaches for diseases caused by abnormal zinc metabolism. Our preliminary results have established the powerful C. elegans model system for studies of zinc metabolism by the development of culture conditions that permit manipulation of dietary zinc, the creation of assays that measure zinc metabolism, and the identification of mutations in new genes that affect zinc metabolism. These results support three innovative hypotheses. (1) CDF-2 plays a critical role in zinc storage and detoxification by transporting zinc into the lumen of lysosome-related organelles. (2) Lysosome-related organelles adopt a bilobed morphology in response to high zinc conditions and provide a source of zinc that is mobilized during deficiency. (3) Histidine ammonia lyase plays an important role in zinc metabolism, and high levels of histidine promote zinc detoxification. To test these hypotheses, we propose two specific aims. Aim 1: Define the role of CDF-2 and lysosome-related organelles in zinc storage. Elucidate how a network proteins including CDF, ZIP and ferroportin function in a coordinated manner to regulate zinc storage and mobilization. Aim 2: Determine the function of histidine ammonia lyase and histidine in zinc metabolism in mammalian cells. Identify and characterize new genes that mediate zinc metabolism in C. elegans and mammals. These experiments build on our accomplishments in the previous grant period that established the C. elegans model system for studies of zinc metabolism. This proposal will extend these discoveries to vertebrate systems and exploit the powerful experimental advantages of C. elegans to elucidate how a network of genes regulates zinc storage and mobilization in a multicellular animal. Several prevalent human diseases such as Alzheimer's disease, stroke and cancer have been associated with abnormalities of zinc metabolism, and the results of these studies may suggest new therapeutic strategies for addressing disorders of zinc toxicity. PUBLIC HEALTH RELEVANCE: Zinc is an essential nutrient that is critical for human health, since zinc deficiency and excess both cause a wide range of health problems. This research will determine how animals protect themselves against excess zinc, and how zinc that is stored in times of excess can be used later in times of deficiency. These studies will suggest new strategies for treating diseases caused by zinc excess or deficiency.