The long-term goal of this project is to establish Dr. Logan as a successful and funded, independent investigator in the field of aging, and in particular, mitochondrial redox homeostasis and brain aging. Dr. Logan joined the laboratory of Dr. William Sonntag to study the mechanisms underlying IGF-1-dependent changes in learning and memory. Dr. Sonntag is a leading authority in the field of neuroendocrine signaling and aging. Dr. Sonntag's laboratory offers a variety of in vivo approaches, which will expand her technical repertoire and allow her to become a well-rounded research scientist. The research strategy outlined incorporates in vitro techniques used to study mitochondrial metabolism with the in vivo techniques in the Sonntag laboratory. The training program includes a mixture of hands-on laboratory training, journal clubs and mentoring interactions with Dr. Van Remmen and members of the Oklahoma Nathan Shock Center. Dr. Logan will receive specialized training in mitochondrial function and signaling networks directly relevant to this area of research. This program will ensure that Dr. Logan transitions to an independent investigator in the field of aging research. The short-term objective of this application is to enhance the candidate's knowledge of mitochondrial metabolism and redox homeostasis and long-term to enable the candidate, as a newly-hired faculty member, to secure protected time for research activity, establish new collaborations, and pursue a novel line of independent research that results in competitive grant proposals. Preliminary data performed by Dr. Logan indicate that IGF-1 regulates energy levels in astrocytes rather than neurons; loss of IGF-1 signaling reduces energy charge in astrocytes, increases mitochondrial ROS that when chronically sustained leads to learning and memory impairments. This proposal expands these novel findings to better understand how IGF-1-regulated mitochondrial bioenergetics and redox signaling contribute to age-related cognitive decline. The overarching hypothesis is that aberrations in astrocytic redox and energy homeostasis contribute to cognitive deficits with age. The following aims are proposed: 1) Determine whether IGF-1R signaling deficiency impairs astrocyte mitochondrial function and bioenergetics; 2) Decipher the molecular regulation of redox homeostasis in astrocytes with IGF-1R signaling deficiency; and 3) Delineate the functional consequence of IGF-1R signaling in astrocytes on learning and memory. The studies that have been proposed will explore pathways that increase the risk for neurodegenerative disease, contribute to cognitive impairment and potentially be targeted to improve the quality of life for older individuals.

Public Health Relevance

Cognitive decline is a debilitating aspect of aging and age-related neurodegenerative diseases that is closely associated with the decline of a key trophic factor, insulin like growth factor (IGF-1). We have found that IGF-1 signaling deficiency in astrocytes decreases energy charge, increases mitochondrial reactive oxygen species (ROS) and impairs hippocampal-dependent learning. By exploring mechanisms underlying astrocytic dysfunction with age, we will elucidate new avenues for therapy for cognitive decline with age and in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
1K99AG056662-01A1
Application #
9527594
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Dibattista, Amanda
Project Start
2018-09-30
Project End
2020-08-31
Budget Start
2018-09-30
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104