2018 Center on Aging Pilot Grant Program Recipients
The Center on Aging Steering Committee received 14 pilot grant submissions in 2018. We had a difficult challenge selecting from this group of meritorious projects! We are pleased to announce the following recipients of 2018-19 Pilot Grant funding:
Robert Campbell, PhD
Co-I Matthew Rondina, MD, MS
Co-I Anthony Donato, PhD, MS
Inflammation in Aging Increases Platelet Hyperactivity and Thrombosis
Aging is accompanied by a decreased tolerance to physiological stress, which promotes
increased susceptibility to inflammatory illnesses. Critical illnesses such as sepsis,
disportionately effect people over the age of 65, leading to increased morbidity and
mortality in older adults. Thrombosis is a common complication from sepsis, contributing
to organ failure and death. Emerging evidence supports the concept that dysregulated
platelet functions mediate the injurious host response during inflammation. Nevertheless,
the molecular mechanisms and functional consequences of dysregulated platelet functions during
aging and inflammation remain incompletely understood. Our proposal, entitled "Inflammation
in
Aging Increases Platelet Hyperactivity and Thrombosis" will identify new pathways
by which inflammatory agonists, including, interferons (IFNs) regulate gene expression
in platelets and their parent cell, the megakaryocyte (MK) in aging. Our preliminary
studies have identified that the expression of IFITM3 is robustly induced in human
platelets during sepsis. Interestingly, MKs and platelets from aged human and mice
express more IFITM3 after IFN stimulation compared to younger controls. Our data suggest
that IFITM3 promotes fibrinogen endocytosis in MKs and platelets, leading to platelet
hyperreactivity and thrombosis. Our findings also suggest in aging and during inflammatory
stress, the mammalian target of rapamycin (mTOR) pathway is activated, triggering
IFITM3 synthesis and thrombosis. The expression and function of IFITM3 in MKs and
platelets and its regulation by mTOR is a pathway not previously examined. In this
proposal, we will couple studies in older and younger septic patients with in vitro
and in vivo murine models using aged mice. These complementary human and murine studies
will allow us to establish clinical relevance, while also dissecting the mechanisms
by which IFITM3 governs MK and platelet function during inflammation. These studies
are translational and innovative as IFITM3 regulation of endocytosis, a process critical
for cellular function has not previously been studied in MKs, platelets, or - for
that matter - any primary human cells. They will also determine for the first time
whether if aging alters the effect of inflammatory agonists on transcriptional and
translational events in MKs and platelets. This work will test an important functional
hypothesis and clarify pathophysiologic mechanisms of thrombosis aging during inflammation.
Vincent Koppelmans, PhD
Co-I Kevin Duff, PhD
Co-I Sara Weisenbach, PhD
Co-I Robert Welsh, PhD
Ecological Assessment of Emotion Regulation in Amnestic Mild Cognitive Impairment
Emotion regulation (ER) is important for emotional well-being and partly relies on
intact neurocognitive functions. Not much is known about ER in older adults with or
without amnesitc Mild Cognitive Impairment (aMCI). Cognitive problems in aMCI may
further hamper ER in these subjects and thus reduce emotional well-being. This study
will assess differences in emotion regulation ER strategies and mood fluctuation between
healthy older adults, and a group of demographically-matched subjects with aMCI. Because most
ER measures have not been validated in older adults with or without aMCI, we will
use ecological momentary assessment (EMA) to measure ER in everyday life and relate
that to identical and similar
measures collected in a lab environment. With the EMA we will measure mood and ER
at on multiple days at several time points. We will use this data to assess the ecological
validity of the conventional ER measures using the EMA ER data. In a next step we
will relate the conventional and EMA ER data to measures of cognitive functioning
to test if executive functioning and ER are differentially related in healthy older
individuals and individuals with aMCI. Within subjects with aMCI we will look if the
extent of executive dysfunction relates to type and extent of use of ER strategies.
Finally, we will use the EMA data to calculate an index of mood fluctuation. Mood
fluctuation cannot be derived from conventional emotion self reports, but could provide
new information on the differences in emotional well-being and ER between healthy
older adults and individuals with aMCI.
Michelle Litchman, PhD, FNP-BC, FAANP
Co-I Nancy Allen, PhD, ANP-BC
A Feasibility Study of Older Adults and their Care partners using RT-CGM Share
This Center on Aging Pilot Grant will examine the use of 1) real-time continuous glucose
monitoring (RTCGM) in older adults with and without cognitive decline and comorbid
type 1 diabetes and 2) RT-CGM data sharing with care partners via mobile app. Adults
with type 1 diabetes are living longer. Age related changes, coupled with diabetes-related
complications, such as hypoglycemia and cognitive decline, places older adults at
risk for cardiac events, loss of consciousness, falls, seizures, and hospitalizations.
There is little information about older adults with cognitive decline who use RT-CGM
or older adults who share RTCGM data with care partners. The objective of this research
is to determine if older adults with and without cognitive decline can effectively
share RT-CGM information with care partners to improve hypoglycemia and glycemic variability.
Our three aims are: 1) adapt a RT-CGM data sharing training manual for older patients
and care partners that includes the technical and behavioral components of this technology,
2) evaluate the feasibility, acceptability, adherence and clinical outcomes of RT-CGM
with data sharing and 3)
evaluate hypoglycemia confidence, quality of life and RT-CGM data sharing experience.
This study is a critical first step in determining how older adults and care partners
can use RT-CGM with data sharing to improve hypoglycemia and glucose variability.
Findings from this study will be used as preliminary data to develop a fully powered
randomized control trial.
Marc Porter, PhD
Co-I Phillip Kithas, MD, PhD
Sensitive Detection of Age-Related Biomarkers Using Surface-Enhanced Raman Scattering
Preventative or curable age-related diseases such as heart disease and diabetes can be successfully treated if detected early in their development via routine physician visits and preventative screening. An emerging area in geriatric medicine centers on the detection of advanced glycation end-products (AGEs), which are proteins or lipids that become glycated as a result of exposure to sugars. AGEs have been linked to the development or worsening of conditions such as diabetes, Alzheimer’s and heart disease. Currently, there is no “gold standard” method to screen for AGEs. We propose the development of a multiplexed immunosorbent assay for three abundant blood-borne AGEs – carboxymethyllysine (CML), methylglyoxal 5-hydro-5-methylimidazolone (MG-H1), and glycated hemoglobin (Hb1Ac). This platform, which is based on an extensive body of work at the University of Utah, provides a snapshot of serum AGE levels and can be used for screening or monitoring of therapeutic interventions.
Karen Schliep, PhD, MSPH
Association Between Women's Reproductive Health and Later Dementia
Hypertensive disorders of pregnancy (HDP), including preeclampsia, is the leading
cause of fetal and maternal morbidity and mortality, complicating 3–10% of all pregnancies.
Little is known regarding the association between HDP and long-term adverse maternal
neurological outcomes with similar inflammatory vascular etiologies, including the
two most common forms of dementia—Alzheimer’s disease (AD) and
vascular dementia (VaD). However, emerging experimental models demonstrating distinct
etiologies between HDP and AD as well as HDP and VaD make a strong biological case
for such an association. An estimated 5.4 million Americans currently suffer from
dementia, two-thirds of whom are women. As the US aging population increases, prevalence
of dementia is expected to approach 16.0 million cases by 2050. Why AD and VaD disproportionately
affect women is not known. This project sets out to test our central hypothesis that
women with versus without HDP will have increased risk for dementia, with four specific aims:
1) increase diagnostic accuracy of AD, VaD, and other dementias within a large population
database containing routinely collected health information; 2) investigate the association,
and dose-response, between HDP and AD and/or VaD; and 3) evaluate the mediating effects
of depression on HDP–AD and/or VaD risk. Our study proposes to use four complementary,
unique, and rich data resources. Three have notably low measurement error in regards
to definitive dementia diagnoses. The fourth has low sampling error: a statewide database
of over 11 million individuals with linked family history, sociodemographic, and medical/vital
records. In Aim 1, we use a machine learning approach to develop AD and VaD classification models
to analyze longitudinal, individual-level routinely collected health information data
to maximize both the sensitivity and specificity of identifying the gold standard
AD and/or VaD cases. In Aim 2 and 3, after
optimally classifying and linking AD/VaD diagnoses within UPDB, women with HDP will
be identified (n ~ 65,000) and then tested for risk for AD and/or VaD, taking into
account important confounding factors and mediating effects of depression. The results
of the aims will inform a life-course approach to women’s health research, with a
goal of contributing to our understanding of gender disparities in dementia risk.
This
research will prepare the research team to design and implement a novel R01 application
to explicate the mechanistic relationship between women’s reproductive health and
subsequent dementia risk leading to timely interventions targeting those with a high-risk
maternal health history.
Lauren Theilen, MD
Co-I Russ Richardson, PhD
Co-I Michael Varner, MD
Vascular Aging in Women with a History of Recurrent Hypertensive Disease of Pregnancy
Women with a history of hypertensive disease of pregnancy (HDP) have increased risks
for chronic diseases later in life. Cardiovascular disease is the leading cause of
death among women in the United States, and HDP is now recognized as an important
risk factor for the later development of cardiovascular disease. Our data have shown
that women who have had HDP in more than one pregnancy (recurrent HDP) have significantly
increased risks for death from heart disease and stroke before the age of 50; however,
an important knowledge gap remains regarding the timeline and pathophysiology of cardiovascular
risk following HDP. We hypothesize that women with recurrent HDP will have an accelerated
vascular aging phenotype that may be identified before the onset of clinical cardiovascular
disease via noninvasive studies of vascular function. To test this hypothesis, we propose
to identify a cohort of women with a history of recurrent HDP who delivered their
first affected pregnancy 10-15 years ago (exposed women). We will match them to women
who have also had more than one pregnancy, but who have no history of HDP (unexposed
women). We will test both groups of women in order to determine if exposed women,
compared to unexposed women, 1) exhibit
increased arterial stiffness, as measured by pulse wave velocity, and 2) exhibit impaired
endothelial function, as measured by the hyperemic response to passive leg movement.
Our pilot study will provide preliminary data to guide subsequent investigation regarding
the underlying pathophysiology and prevention of cardiovascular disease among women
with a history of HDP.