BLRD Research Career Scientist Award Application

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Alzheimer's disease (AD) is a major public health concern. Veterans are at a higher risk for dementia late in life due to in-service exposures and epidemiological factors. The goal of Dr. Galvan’s research is to understand the molecular and biochemical alterations that cause AD, with a focus on those that link aging to AD and potentially other dementias, and to identify interventions to prevent or treat AD. Advanced age is, by far, the greatest risk factor for AD. A VA Merit-funded project (1I01 BX002211-01A2) in Dr. Galvan’s lab focused on the use of rapamycin, the first drug that was experimentally proven to slow aging in mice, to treat and/or block progression of AD. Dr. Galvan’s Merit-funded work led to the first clinical trial of rapamycin in Alzheimer’s disease and established a novel area of research in the vascular etiology of AD by revealing novel mechanisms of vascular contributions to cognitive impairment and dementia (VCID), an area of high relevance to Veterans’ health and of specific interest for NIA and NINDS. Pathogenic tau protein is causally implicated in AD. Based on evidence for pathogenic tau accumulation in vasculature of AD brain provided for the first time by Dr. Galvan’s team, a second VA Merit-funded project in Dr. Galvan’s lab (5 I01 BX002211-06) will define mechanisms of pathogenic tau-induced brain vascular dysfunction. Dr. Galvan’s studies are important for Veterans’ health because they will test immunotherapy targeting pathogenic tau, that can be combined with immunotherapy targeting amyloid-beta, recently approved by the FDA, to efficaciously treat AD. Molecular damage during aging leads to cellular senescence. Senescent astrocytes accumulate in aging and are markedly increased in AD. Dr. Galvan’s laboratory showed, for the first time, that pathogenic tau enters astrocytes, where it potently induces cellular senescence. Collaborative studies (1RF1AG068283-01) of Dr. Galvan and Dr. Holly Van Remmen (OKC VA Health Care System, VAHCS) will define mechanisms of pathogenic tau-induced astrocyte senescence, understand its contribution to AD etiology, and test drugs that kill senescent cells and immunotherapy targeting pathogenic tau to treat AD. With her recent move to OKC VAHSC and affiliated institution University of Oklahoma Health Sciences Center (OUHSC), Dr. Galvan expanded her established collaboration with Dr. Van Remmen and with Dr. Arlan Richardson (OKC VAHSC) on the role of necroptosis in the activation of cellular senescence in brain in aging and AD. Dr. Galvan’s move to OKC VAHCS promoted her established collaboration with Dr. Zoltan Ungvari (OUHSC) on brain microvascular mechanisms of AD. Funded collaborative work of Dr. Galvan with Dr. Ungvari and with external investigators Dr. Viviana Perez (OSU, now NIA) (1RF1AG057964) and Dr. Rakez Kayed (UTMB) provided first evidence for pathogenic tau transmission to brain vascular endothelial cells, accumulation of pathogenic tau in endothelial cells and endothelial cell dysfunction and senescence in AD. These studies, currently in 2nd round of review in Nature Communications, showed that tau immunotherapy may be used to treat vascular tauopathy in AD. Dr. Galvan is co-Investigator in 2 additional NIH grants, an Alzheimer’s Association/Gates Foundation grant and a Michael J. Fox Foundation grant. She serves as co-Director of the Center for Geroscience and Healthy Brain Aging at OUHSC, and is involved in leadership of the NIH/NIA P30 Oklahoma Nathan Shock Center of Excellence in the Biology of Aging (NSC) at OUHSC and OMRF. She served as Core Co-Leader in the NSC and as Associate Director of the NIA T32 Training Program in the Biology of Aging at her prior affiliated institution, UT Health San Antonio, and in the GRECC at her prior station, South Texas VAHCS. Dr. Galvan has received eight awards, is President of the American Aging Association, and serves as Co Editor-in-Chief of Geroscience. Her work has been cited over 6,400 times with h-index=45. She served in VA BLRD NURD and NURC review panels and is a standing member in the NIH/CSR CMAD Study Section. Dr. Galvan mentors or mentored a CDA-2 trainee, 4 junior faculty and clinician/scientists, 4 graduate or MD/PhD students, 2 MD student fellows, and 4 postdoctoral fellows among other trainees, most of which have gone on to successful careers in science and science-related professions.