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

犬尿氨酸：年龄相关的骨量下降与肾功能之间的潜在联系

• 批准号: 10456103
• 负责人: Debra Irsik
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456103
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Advisory Committees; Advocate; Affect; Age; Aging; Albuminuria; American; Antioxidants; Aryl Hydrocarbon Receptor; Award; Biology; Blood Pressure; Bone Density; Bone Marrow Stem Cell; Cells; Certification; Chronic; Communication; Data; Degenerative Disorder; Dietary Intervention; Dihydroxycholecalciferols; Discipline; Doctor of Philosophy; Dual-Energy X-Ray Absorptiometry; Elderly; Ensure; Essential Amino Acids; Excretory function; Experimental Designs; Faculty; Fibroblast Growth Factor Receptors; Fibrosis; Fracture; Funding; General Population; Gerontology; Glomerular Filtration Rate; Goals; Health; Health Care Costs; Histology; Hormones; Hospitalization; Immune; Impairment; Infiltration; Inflammation; International; Kidney; Knowledge; Kynurenine; Laboratories; Lead; Learning Skill; Link; Longevity; Mediating; Mentors; Mentorship; Mixed Function Oxygenases; Molecular; Morbidity - disease rate; Mus; Osteoporosis; Outcome; Oxidative Stress; Oxides; PTH gene; Pathway interactions; Phenotype; Play; Positioning Attribute; Premature aging syndrome; Principal Investigator; Process; Protein-Restricted Diet; Public Health; Quality of life; Regulation; Renal Mass; Renal function; Renal glomerular disease; Research; Research Personnel; Research Training; Risk; Role; Scientist; Serum; Serum Calcium Level; Signal Transduction; System; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; Underrepresented Minority; Veterans; Vitamin D; Woman; Work; age related; aged; bone; bone aging; bone health; bone loss; bone mass; bone metabolism; calcium phosphate; career; career development; cost estimate; experimental study; feeding; fibroblast growth factor 23; high risk; innovation; inorganic phosphate; kidney dysfunction; kidney fibrosis; large datasets; meetings; member; mortality; oxidation; rate of change; receptor; stem cell proliferation; tenure track; young adult

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.

项目概要 骨质疏松症是一个影响 4400 万美国人的重大公共卫生问题，估计造成 170 亿美元的损失 2001 年。尤其是老年人的骨折会导致显着的发病率和死亡率。 衰老过程中骨质流失的肾脏机制是本应用的重点。肾脏负责。 用于维生素 D 合成，有助于控制骨生成的 FGF23 水平。 及其共同受体 Klotho 有助于调节这些过程以及这些因素或其任何因素的失调 下游信号会导致骨质流失，也会损害肾功能，这也可能导致骨质流失。 与衰老相关的骨质流失。然而，骨质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，是一种有效的抗氧化剂，但其含量会随着年龄的增长而降低。 然而，其稳定的氧化代谢物犬尿氨酸随着年龄的增长而增加，并抑制骨髓干细胞 我们实验室的工作表明，给小鼠喂食犬尿氨酸会导致骨质流失。 中心假设是犬尿氨酸水平升高会导致衰老表型，从而导致骨质流失 和通过 FGF23/αKlotho 途径的肾功能障碍。 Irsik 博士将在拥有信号专业知识的 Wendy Bollag 博士的指导下进行这些实验 十几年来一直受到 VA Merit 资助，以获取衰老方面的知识。 研究期间，她将努力获得老年学证书，并与她职业生涯的成员合作 获得衰老研究实验设计专业知识的咨询委员会将提供以下方面的专业知识： 衰老和骨骼研究，Carbone 博士是退伍军人骨骼问题方面的专家，Dong 博士受到认可 Irsik 博士将通过学习表演来扩展她目前的研究技能。 通过 Bollag 博士和 Isales 博士的共同努力，将提供 DXA、CT 和骨组织学检查。 协助她的肾脏研究，Carbone 博士将教她如何使用通过以下方式获得的大型数据集： 她每周都会与 Bone Group 的所有成员进行互动，其中包括精英和普通成员。 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。 她每年至少参加两次国际会议（ASBMR、ASN、GSA 或实验生物学）的研究。 Bollag 博士指导过许多学员，她的指导将促进她向独立的过渡 她提供了成功女性博士科学家的视角。 Isales 博士是一名临床医生，多年来一直倡导保护代表性不足的少数族裔研究人员。 这两位研究人员拥有大约 30 年的成功合作记录， 将有助于确保 Irsik 博士获得必要的指导，为独立的研究做好充分准备 CDA2 奖项将用于获取她在衰老领域的研究生涯所需的初步数据。 申请自己的 VA 优异奖，使她获得第一个终身教职。