Complexity Loss, Aging and the Dynamics of Frailty

描述（由申请人提供）：Madalena Costa博士的职业目标是成为一名独立的学术研究者和教师导师。她的长期目标是：(i)了解健康中非线性生理控制的基本机制及其随衰老和虚弱而退化的基本机制；（ii）开发一类新的动态生物标志物，量化综合生理功能，并提供传统探针无法获得的病理生理学信息；（iii）确定这些生物标志物随时间动态行为中编码的信息的价值，用于风险分层和评估旨在逆转或延缓病理性衰老的治疗干预措施。她的工作涉及统计物理学、生物工程、生理学和衰老生物学等跨学科领域。这项跨学科工作的两个新兴主题是，健康系统以稳健性和适应性为特征，表现出最复杂的多尺度动态，特别是衰老和虚弱综合征，其特征是复杂的多尺度变异性和适应能力的丧失。在导师的支持下，他们的工作跨越了生物学、临床医学、物理学、非线性动力学和生物统计学的不同领域，这些都是基础广泛的培训计划的重要方面，Costa博士建议追求一个职业发展计划，这将使她能够进一步发展她在复杂系统方面的专业知识，并结合最先进的衰老生物学知识和临床虚弱综合征。她的基础研究将解决以下具体目标：1)通过开发量化多尺度波动的动态生物标志物来阐明综合生理控制的非线性机制；2)验证从细胞到器官的代表性系统中生理调节机制的动态复杂性随着衰老而退化的假设；3)验证生理系统复杂性随时间的丧失可以预测整体健康状况退化和随后的虚弱发展的假设。她还将利用她的经验制定一个复杂信号定量分析的培训计划。相关性（见说明）：这项工作很重要，因为它使用新的方法和技术来解决一个重大的公共卫生问题，即老年人虚弱，这影响到数百万美国人和世界各地的其他人，造成大量发病率和死亡率，并造成数十亿美元的医疗保健费用。

DESCRIPTION (provided by applicant): Dr. Madalena Costa's career goal is to become an independent, academic investigator and faculty mentor. Her long-range goals are: (i) to understand basic mechanisms underlying nonlinear physiologic control in health and their degradation with aging and frailty, (ii) to develop a new class of dynamical biomarkers that quantify integrative physiologic function and give information about pathophysiology not obtainable with traditional probes, and (iii) to determine the value of the information encoded in the dynamical behavior of these biomarkers over time for risk stratification and the assessment of therapeutic interventions designed to reverse or retard pathologic aging. Her work is at the interdisciplinary interfaces of statistical physics, bioengineering, physiology, and the biology of aging. Two emerging themes of this interdisciplinary work are that healthy systems, which are marked by robustness and adaptability, exhibit the most complex multiscale dynamics, and that aging and the frailty syndrome in particular, are marked by a loss of complex multiscale variability and adaptive capacity. With the support of mentors, whose work spans diverse fields of biology, clinical medicine, physics, nonlinear dynamics and biostatistics that are essential facets of a broad-based training program, Dr. Costa proposes to pursue a career development plan that will enable her to further develop her expertise in complex systems in concert with state-of-the-art knowledge of the biology of aging and the clinical syndrome of frailty. Her basic research will address the following specific aims: 1) to elucidate nonlinear mechanisms of integrative physiologic control by developing dynamical biomarkers that quantify multiscale fluctuations; 2) to test the hypothesis that the dynamical complexity of physiologic regulatory mechanisms degrades with aging in representative systems ranging from the cellular to organ, and 3) to test the hypothesis that loss of complexity in physiologic systems over time can be predictive of overall health status degradation and subsequent development of frailty. She will also use her experience to develop a training program in quantitative analysis of complex signals. RELEVANCE (See instructions): This work is of importance because it uses novel approaches and technologies to address a major public health problem, namely frailty in the elderly, which affects millions of Americans and others worldwide and is responsible for substantial morbidity and mortality and for billions of dollars of healthcare costs.