Emerging Topics & Early-Career Research Support

Through the Geroscience Center of Biomedical Research Excellence (CoBRE) at the Oklahoma Center for Geroscience and Healthy Brain Aging in Oklahoma City, early-career researchers can find support for investigations into emerging topics in the field of aging and age-related disease.

Research Services & Resources

In addition to partnering with organizations such as Oklahoma Nathan Shock Center on Aging for certain core services, the Oklahoma Center for Geroscience and Healthy Brain Aging supports researchers with a wide range of tools, services and resources for collaborative projects, including:

Early-Career Investigators & Topics

Oklahoma Center for Geroscience and Healthy Brain Aging currently supports four early-career researchers, also known as promising junior investigators (PJIs), and one Year 3 pilot project. Current researchers and projects include:

  • Dr. Andriy Yabluchanskiy – Diabetes-induced cognitive decline with age: Novel neurovascular mechanisms
  • Dr. Heather Rice – APP function in glia and implications for Alzheimer’s therapies
  • Dr. Amanda Sharpe – The role of proopiomelanocortin neurons in age-related cognitive decline
  • Dr. Shannon Conley – IGF-1, smooth muscle plasticity, and pathogenesis of cerebral microhemorrhages in aging

The Year 3 Pilot awardee, Dr. Anthony Burgett, studies oxysterol-binding protein as a druggable target to reverse age-related decline.

Abstracts of Current Research Studies

Review abstracts of each investigation below.

Diabetes-induced cognitive decline with age: Novel neurovascular mechanisms

Dr. Andriy Yabluchanskiy, PJI

One of the consequences of type 2 diabetes mellitus (T2DM) in the elderly that is largely ignored is that the risk of cognitive impairment increases significantly with age. Individuals with T2DM have a 2.5-fold greater risk of cognitive impairment compared to non-diabetic older subjects. Importantly, both aging and T2DM have been reported to induce a complex stress response termed cellular senescence, which exacerbates age-related functional impairments by altering the secretory phenotype of cells, including astrocytes. Although astrocytes have numerous functions within the brain, one critical function is to regulate local cerebral blood flow. Upon neuronal stimulation, astrocytes release eicosanoid gliotransmitters (EETs) that directly relax vascular smooth muscle cells, allowing increased blood flow to support increased neuronal activity.

Neurovascular coupling (NVC) depends on a balance between astrocytic production of vasodilator and vasoconstrictor lipid mediators. NVC is impaired with age and has been shown to be an important contributor to age-related cognitive decline.

In this application, we propose that cellular senescence is a fundamental process of cognitive decline with age and that T2DM accelerates the development of the senescent phenotype in astrocytes, resulting in a more profound impairment in NVC and cognitive dysfunction than occurs in aging animals alone.

Our hypothesis is that the development of T2DM in aging animals promotes astrocytic senescence, which exacerbates the age-related dysregulation of EETs, leading to neurovascular uncoupling and cognitive impairment. The following aims are proposed: Aim 1: Test the hypothesis that the development of T2DM in aging animals exacerbates the age-related dysregulation of astrocytic eicosanoid gliotransmitters, neurovascular coupling and cognitive function. Aim 2a: Assess whether T2DM results in increased astrocyte senescence in aging mice. Aim 2b: Test the prediction that removal of senescent cells improves NVC responses in older animals with T2DM.

Our hypothesis predicts that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse) or by pharmacological means (ABT263) will result in fewer senescent astrocytes, better NVC responses and improved cognitive function. Identifying the role of astrocytic pathways in the adverse neurovascular and cognitive outcomes of T2DM and aging could identify novel strategies for mitigating these deleterious complications.

APP function in glia and implications for Alzheimer’s therapies

Dr. Heather Rice, PJI

Alzheimer’s disease (AD) is the most common cause of dementia, affecting one in three individuals over the age of 85. Mutations in either Amyloid Precursor Protein (APP) or Presenilin lead to rare, early-onset, familial AD. In the more common, sporadic form of AD, a large proportion of genes that place the individual at risk for AD are expressed primarily in glia and are associated with neuroinflammation.

Accordingly, the relationship between Aβ metabolism and neuroinflammation has been under intensive investigation in the field; however, the responses of glia to other APP proteolytic products besides Aβ remain unknown. The shed APP ectodomain, known as secreted APP (sAPP), has been shown to have therapeutic benefits in AD mouse models. Thus, understanding the role of sAPP in disease processes could lead to novel therapeutic approaches, but a lack of insight into the molecular basis of APP function has hampered these efforts. To overcome this obstacle, we will leverage our recent discovery that the secreted APP (sAPP) fragment functions as a ligand for the GABA type B Receptor subunit 1a (GABABR1a).

Supporting an anti-inflammatory role for sAPP, elevated astrogliosis has been observed in mice lacking APP or ADAM a sheddase which releases sAPPα. While the function of GABABR is best established in neurons, GABABR is expressed in astrocytes and microglia and that GABABR activation in glia suppresses pro-inflammatory signaling. The binding of sAPP to the sushi domain (also known as complement control protein (CCP) module) of GABABR1a also points to the potential for other sushi/CCP domain-containing proteins in the complement control pathway to mediate sAPP activity in glial cells.

Thus, our central hypothesis is that sAPP has anti-inflammatory actions in glial cells mediated by the GABABR and other sushi domain-containing proteins in the complement control pathway; thereby, small synthetic peptides designed to mimic sAPP binding can counteract Aβ-induced neuroinflammation in AD. To test this hypothesis, we will interrogate the glial responses to sAPP-GABABR signaling (Aim 1) and screen for additional CCP/sushi domain-containing sAPP interactors (Aim 2). Finally, we will test the ability of small synthetic peptides which mimic sAPP binding to rescue glial phenotypes in the AppNL-G-F knock-in mouse model of AD (Aim 3).

The role of proopiomelanocortin neurons in age-related cognitive decline

Dr. Amanda Sharpe, PJI

Cognitive decline is a common sequela of mammalian aging, from rodents to humans. As it often results in the inability to live independently, slowing or preventing the loss of cognition with age would significantly increase the quality of life for older adults. While the etiology of age-related cognitive impairment is unknown, there is increasing evidence that age-related changes in neurotransmitters may play an important role.

Neurotransmitters produced from proopiomelanocortin (POMC) are of particular interest because they modulate cognition, metabolic rate and other age-related phenotypes, and their levels are known to decrease with age. Furthermore, when administered systemically, or into the brain, they improve memory, attention, and cognition and delay the decline in cognition in mouse models of Alzheimer’s disease. However, which POMC-producing neurons are responsible for the age-related decline in brain POMC, the mechanism by which this occurs, and its contribution to age-dependent cognitive decline are not known. Our studies will yield insight into mechanisms responsible for age-related changes in POMCHipp neurons and reveal whether interventions that delay aging act, in part, by modulating these neurons. Filling these gaps in knowledge is essential for development of interventions to reverse cognitive aging.

The proposed work is enabled by a novel combination of technology, including retrograde labeling of POMCHipp neurons and mouse genetic models that together allow us to specifically target these neurons. This will allow us to analyze age-dependent changes in the number and projection density (Aim 1) and gene expression (Aim 2) of POMCHipp neurons that may provide insight into the decline in cognition with age. We will further determine whether these changes can be reversed by treatment with rapamycin, a drug that increases lifespan in mice while ameliorating age-related declines in cognition, as well the age-related dysfunction of Arc POMCPVN neurons. Finally, in Aim 3 we will specifically activate or inhibit the function of Arc POMCHipp neurons and measure the impact on cognition.

Our approach is highly innovative, will define the role of POMCHipp neurons in the mechanisms responsible for cognitive decline with age and provide a framework for studies to develop interventions to reduce age-related cognitive decline. This PJI project will provide the preliminary data, mentorship, and resources for the development of a competitive, independent research grant proposal in the field of geroscience.

IGF-1, smooth muscle plasticity, and pathogenesis of cerebral microhemorrhages in aging

Dr. Shannon Conley, PJI

Cerebral microhemorrhages (CMH) result from rupture of small intracerebral blood vessels and progressively impair neuronal function. The incidence of CMH dramatically increases with age and hypertension and is a major cause for age-related cognitive decline. Cognitive decline caused by CMH has severe impacts on quality of life yet remains untreatable. CMHs occur due to increased vascular fragility but underlying mechanisms are unknown, and thus therapeutic interventions to mitigate CMHs are not available.

Blood vessel integrity requires plasticity of vascular smooth muscle cells (VSMCs), which exhibit an adaptive switch from a highly contractile to a protective anti-fragility phenotype in response to stress. Aging fundamentally alters VSMC phenotypic switching, suppressing the adoption of this protective VSMC phenotype. In contrast, insulin-like growth factor (IGF)-1 has vasoprotective effects and promotes adoption of the protective anti-fragility phenotype, but circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels increase the risk for cerebromicrovascular disease and promote the development of CMH in our rodent models, supporting a role for IGF-1 deficiency in age-related vascular fragility.

Our hypothesis is that impaired VSMC phenotypic switching due to IGF-1 deficiency has a fundamental role in increased cerebrovascular fragility and development of CMH with age. Aim 1 will test the hypothesis that increased CMH in aging is due to vascular fragility arising from decreased IGF-1 signaling in VSMCs. Development of CMH, associated neurological/gait defects, and VSMC phenotype will be compared in mice with VSMC-specific disruption of IGF-1 signaling, mice with overall disruption of IGF-1 signaling, and aged mice coupled with IGF-1 supplementation/rescue. Aim 2 will use cultured aged, young, and IGF-1 receptor knockdown VSMCs to test the hypothesis that IGF-1 signaling is required for VSMC cellular adaptation to hemodynamic stress and will evaluate novel mechanisms mediated by the transcription factors Tbx15/18 for this regulation. Aim 3 will test the hypothesis that VSMC phenotypic heterogeneity influences the development of CMH. VSMCs exist in a heterogeneous pool in which multiple phenotypes co-exist, determined based on growth factors including IGF-1 and other stimuli in the extracellular space, but the characteristics of this heterogeneity in cerebral arteries is unknown. VSMC lineage-tracing genetic mouse models of aging and IGF-1 deficiency, coupled with single-cell RNA sequencing will be used to characterize VSMC heterogeneity. Newly discovered pro- and anti-fragility VSMC phenotypic states will be correlated with location of CMH bleeds to test the hypothesis that CMHs occur primarily in regions where VSMCs show a maladaptive phenotype.

The scientifically and technically innovative studies proposed here will significantly enhance our understanding of the role of IGF-1 deficiency in the development of CMH and will provide critical insight into cellular mechanisms underlying it, both of which are critical for the development of effective therapies.

Year 3 Pilot

Oxysterol-binding protein as a druggable target to reverse age-related disease

Dr. Anthony Burgett, PJI

Understanding and ultimately therapeutically intervening in human age-related disease requires identifying dynamic and changeable age-related cellular and biological processes. Two promising cellular processes associated with aging disease phenotype are the mTOR1C pathway and the systems ensuring fidelity in RNA processing, including the nonsense-mediated decay (NMD) pathway. Our interdisciplinary chemistry and cell biology research group has recently discovered that the human protein oxysterol-binding protein (OSBP) regulates mTOR1C activity and is capable of inversely inducing the NMD pathway in cells. OSBP is a non-enzymatic cytoplasmic lipid-binding protein with a still-not-fully-understood cellular function. Recently, OSBP has been identified as being required for the replication of a broad range of mRNA viruses.

Through our work on studying OSBP in viral replication, our published research indicates OSBP functions as a master lipid sensor, informing the cell of lipid levels at specific organelle membranes. We have discovered that transient, low-dose treatment with the OSBP-targeting compound OSW-1-compound induces a long-term, multigenerational repression of OSBP, and the cells with repressed OSBP compound induces autophagy and slows global protein translation through altering mTOR1C activity. The long-term repression of OSBP, triggered by OSW-1, has no effect on cellular division, viability, or morphology in a panel of different cell lines.

Our unpublished results also show that chemical inhibition of OSBP induces a pronounced increase in the expression of many components of the NMD pathway, and our hypothesis, backed by recent reports, indicates that NMD is sabotaged during mRNA viral replication in order to allow the viral RNAs to be translated. The potential compound-induced reactivation of NMD could reestablish fidelity in RNA processing and translation in age-related phenotypes.

Our hypothesis is that the role of OSBP in antiviral innate immunity we have helped to define is only a facet of the OSBP role in overall cellular function. We hypothesize that OSBP is a master regulator in ensuring correct function in cellular metabolism and in the fidelity of RNA translation, and that small molecule inhibitors of OSBP capable of inactivating mTOR1C and activating NMD would be a novel and promising therapeutic approach for age-associated phenotypes and age-related disease.

Join Oklahoma’s Geroscience Professionals

As a clinician, educator or researcher working in the area of age-related disease, you’re encouraged to become a member of the Oklahoma Center for Geroscience and Healthy Brain Aging. Join our broad effort to better understand the aging process, reduce disease and improve quality of life as we all get older.

View our leadership team and find OU Health geroscience clinical faculty.

Contact us to learn how you can partner with Oklahoma Center for Geroscience and Healthy Brain Aging.

National Funding Support for Oklahoma

Oklahoma Center for Geroscience and Healthy Brain Aging is funded in part by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health.

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