Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and amelioration of age-related organ dysfunction. The possibility of harnessing stem cells to reverse normal aging raises the question as to how the aging process modulates tissue specific stem cell activity. In the central nervous system, investigating the effect of aging on neural stem/progenitor cell (NPC) function is of particular interest due to the associated onset of cognitive impairments, and lack of neural repair in response to neurodegenerative diseases, such as Alzheimer's disease. During my doctoral work, I discovered that molecular changes occurring in the aging systemic milieu negatively regulate NPC function and cognition. Furthermore, I identified a subset of systemic immune factors - ?2-Microglobulin (B2M), CCL11 and CCL2 -, as potential regulators of neurogenesis and cognitive function. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis. Thus, the goal of this application is to investigate how immune-related molecular changes in the aging systemic milieu regulate NPC function and associated cognitive processes. Specifically, my hypothesis is that systemic age-related immune factors impair neurogenesis, and cognitive processes, by both inhibiting NPC function directly and indirectly via resident immune cells. I will address this hypothesis in three aims: 1.To determine the direct versus indirect effect of systemic age-related immune factors on NPC function in vitro, 2. To examine the direct effect of systemic age-related immune factors on neurogenesis and cognitive function in vivo, 3. To explore the indirect effect of systemic age-related immune factors mediated by resident immune cells on neurogenesis and cognitive function in vivo. Ultimately, I hope that by investigating the cellular and molecular mechanisms underlying impairments in NPC function, we can better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity remaining within the old brain.

Public Health Relevance

The research described in this application aims to elucidate, not only ways by which to enhance the regenerative capacity of the aging brain, but also means by which to counteract the pre-existing effects of aging itself. Ultimately, I hope that by investigating the cellular and molecular mechanisms underlying impairments in neural stem cell function, we can better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity remaining within the old brain.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Early Independence Award (DP5)
Project #
5DP5OD012178-02
Application #
8546253
Study Section
Special Emphasis Panel ()
Program Officer
Basavappa, Ravi
Project Start
2012-09-15
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$367,498
Indirect Cost
$133,671
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Villeda, Saul A; Plambeck, Kristopher E; Middeldorp, Jinte et al. (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659-63