Kynurenine: a potential link between age-related decreases in bone mass and kidney function

项目摘要 骨质疏松症是一个主要的公共健康问题，影响着4400万美国人，估计耗资170亿美元 在2001年。尤其是老年人的骨折可能会导致严重的发病率和死亡率。理解 衰老过程中骨丢失的肾脏机制是这一应用的重点。肾为主因 用于维生素D的合成，有助于控制钙和磷的水平。骨源性成纤维细胞生长因子23 和它的共同受体Klotho帮助调节这些过程，以及这些因子或它们的任何一个的调节失调 下游信号可能导致骨质流失。衰老还会损害肾功能，这也可能导致 与衰老相关的骨质流失。然而，骨骼是否会影响肾功能尚不清楚。 色氨酸是九种必需氨基酸之一，是一种强大的抗氧化剂，但其水平随着年龄的增长而下降； 然而，其稳定的氧化代谢产物犬尿氨酸随着年龄的增长而增加，并抑制骨髓干细胞 扩散。我们实验室的研究表明，喂食犬尿氨酸会导致小鼠骨质丢失。我们的 中心假设是，增强的犬尿氨酸水平导致衰老表型，导致两种骨丢失 并通过FGF23/αKlotho通路发生肾功能障碍。 Irsik博士将在温迪·博拉格博士的指导下进行这些实验，博拉格博士在信号方面拥有专业知识 转导，并已连续十几年获得退伍军人管理局奖励金。为了在衰老中获得知识 研究，她将努力获得老年学证书，并与她的职业生涯成员合作 在老龄化研究中获得实验设计专业知识的咨询委员会。Isales博士将提供以下方面的专业知识 衰老和骨骼研究，而Carbone博士是退伍军人骨骼问题方面的专家，董博士是公认的 因为他在急性肾损伤方面的研究。伊尔西克博士将通过学习表演来扩展她目前的研究技能 DXA，CT和骨组织学通过DRS，博拉格和伊萨莱斯的合作努力。董博士将提供 帮助她进行肾脏研究，Carbone博士将教她如何使用通过 退伍军人事务部。她将每周与骨科小组的所有成员互动，成员包括临床医生和基础医生 来自多个部门和学科的科学家，每年两次展示自己的研究成果。她将向大家介绍 她的研究每年至少参加两次国际会议(ASBMR、ASN、GSA或实验生物学)。 她向独立的过渡将得到博拉格博士的指导，博拉格博士曾指导过许多受训者 为学术研究事业的成功干杯。她提供了一位成功的女博士科学家的视角 而伊萨莱斯博士是一名临床医生，多年来一直主张代表性不足的少数族裔研究人员。 这两名调查人员有大约30年的成功合作记录， 将有助于确保Irsik博士接受必要的指导，以便为独立的 老龄化研究生涯。CDA2奖将被用来获得她需要的初步数据 申请她自己的退伍军人荣誉奖，从而使她获得了她的第一个终身教职。

Project Summary Osteoporosis is a major public health problem affecting 44 million Americans and costing an estimated $17 billion in 2001. Bone fractures in the elderly in particular can result in significant morbidity and mortality. Understanding the renal mechanisms that underlie bone loss in aging is the focus of this application. The kidney is responsible for Vitamin D synthesis and contributes to the control of calcium and phosphate levels. Bone-produced FGF23 and its co-receptor, Klotho help to regulate these processes, and dysregulation in these factors or any of their downstream signals can lead to bone loss. Aging also impairs kidney function which may also contribute to aging-related bone loss. However, whether the bone can affect kidney function is not known. Tryptophan, one of nine essential amino acids, is a potent anti-oxidant but its levels decrease with aging; however, its stable oxidized metabolite, kynurenine increases with age and inhibits bone marrow stem cell proliferation. Work from our laboratory has shown that kynurenine feeding in mice results in bone loss. Our central hypothesis is that augmented kynurenine levels induce an aged phenotype resulting in both bone loss and kidney dysfunction through the FGF23/αKlotho pathway. Dr. Irsik will conduct these experiments under the mentorship of Dr. Wendy Bollag, who has expertise in signal transduction and has been continuously VA Merit-funded for a dozen years. In order to gain knowledge in aging research, she will work towards a certificate in gerontology and collaborate with the members of her career advisory committee to gain expertise in experimental design in aging studies. Dr. Isales will provide expertise in aging and bone research while Dr. Carbone is an expert in bone issues in veterans and Dr. Dong is recognized for his research in acute kidney injury. Dr. Irsik will expand her current research skills by learning to perform DXA, CT and bone histology through the collaborative efforts of Drs, Bollag and Isales. Dr. Dong will provide assistance in her renal studies, and Dr. Carbone will teach her how to work with large datasets available through the VA. She will interact weekly with all the members of the Bone Group, comprised of both clinicians and basic scientists from multiple departments and disciplines, presenting her own research twice a year. She will present her research at a minimum of two international meetings per year (ASBMR, ASN, GSA or Experimental Biology). Her transition to independence will be enhanced by the mentorship of Dr. Bollag, who has guided many trainees to successful careers in academic research. She provides the perspective of a successful woman PhD scientist while Dr. Isales is a clinician who has advocated for under-represented minority researchers for many years. Together these two investigators, who have a successful track record of collaborating for approximately 30 years, will help to ensure that Dr. Irsik receives the mentoring necessary to be well-prepared for an independent research career in aging. This CDA2 award will be leveraged to obtain the preliminary data necessary for her to apply for her own VA Merit Award, thereby allowing her to obtain her first tenure-track faculty position.