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Faculty 
George
Kuchel
Professor of Medicine
Travelers Chair in Geriatrics and Gerontology
Director, UConn Center on Aging
Chief, Division of Geriatric Medicine
kuchel@nso1.uchc.edu
Areas of Interest:
1. Pathophysiology of common geriatrics syndromes
2. Role of inflammatory molecules in mediating the loss of muscle and
neural elements shown to contribute detrusor underactivity and
sarcopenia in frail older adults
3. Design and validation of pleiotropic and targeted interventions
capable of altering the natural history of common geriatrics syndromes.
We are trying to better understand the cellular pathophysiology of
common geriatric syndromes. The overarching goal of our research is to
discover and then test novel interventions capable of altering the
natural history of these common conditions, thus preventing disability
and promoting functional independence in old age.
Geriatric syndromes, such as frailty, mobility problems with falls,
urinary incontinence and delirium, are highly prevalent, multifactorial,
and associated with substantial morbidity, as well as poor outcomes in
the elderly. Unfortunately, the discovery of targeted, mechanism-driven
therapy has been hindered by the fact that these are complex conditions
in which multiple coexisting factors typically contribute to the risk of
disability. Geriatric syndromes present particular a challenge for
mechanistic translational research, since studying a single risk factor
can address only a very small portion of the overall clinical risk,
while efforts designed to address all relevant risk factors in this
manner risk being unfocussed.
With the above considerations in mind, we have pursued a number of
different strategies which have permitted us to examine the nature of
the interactions by which different risk factors for common geriatric
syndromes influence each other in contributing to the development of
disability in late life. We believe that in this manner we are able to
identify specific molecular targets which are particularly promising in
terms of successful intervention development within the framework of
multifactorial geriatric syndromes.
Specific Projects:
1) Pathogenesis of detrusor underactivity, bladder muscle sarcopenia
and urinary retention in the frail elderly.
Detrusor underactivity (DU) is a common geriatric problem which
predisposes the frail elderly to urinary retention and contributes to
the complexity of managing urinary incontinence and related problems in
this population. Nevertheless, its pathophysiology remains unknown,
while management strategies are largely ineffective and palliative.
Since multiple coexisting risk factors contribute to DU, we proposed
that three of the most important contributors – bladder muscle stretch,
lack of estrogen and aging act synergistically via a common shared
downstream pathway. Our studies have now provided considerable evidence
in support of this hypothesis. Moreover, we have discovered that a
cytokine called MIF (macrophage migration inhibitory factor) which is
highly expressed in urothelial cells, plays a crucial role in the
pathways by which bladder muscle stretch, lack of estrogen and aging
contribute to the development of bladder muscle loss (sarcopenia),
fibrosis and axonal degeneration which represent the defining structural
features of DU. The above findings permit us to now perform preclinical
testing of strategies designed to inhibit MIF activity in vivo.
Moreover, they also allow us to use the bladder as a model system
providing new insights into the pathogenesis and treatment of other
geriatric syndromes involving more complex tissues. Collaborators
include Dr Art Hand (UCHC Central EM Facility), Dr Janet McElhaney
(Geriatrics/Immunology), Dr Carol Pilbeam (Geriatrics/Endocrinology), Dr
Pam Taxel (Geriatrics/Endocrinology), Dr John Taylor (Urology) and Dr
Stephen Walsh (Biostatistics).
2) Pathogenesis of skeletal muscle sarcopenia in obesity and
associated frailty.
Recent studies indicate that while weight loss is an important
feature of the best described geriatric frailty phenotype, many frail
elderly individuals are in fact obese. Moreover, obesity and sarcopenia
when present in the same individual appear to synergistically enhance
the future risk of disability. Since obesity has a negative impact on
muscle quality, we have examined aging-related changes in body
composition and mobility in different commonly used inbred mouse
strains. At the same time, we have also undertaken a number of
collaborative studies with Dr David Rowe (Genetics), Dr William Mohler
(Genetics), Dr Anne Kenny (Geriatrics) and Dr Janet McElhaney
(Geriatrics/Immunology). These include efforts designed to define the
lineage origin of cells containing fat deposits within skeletal muscle
tissues, studies examining the impact of various inflammatory mediators
on muscle structure and function, as well as preclinical testing of
specific interventions designed to reverse sarcopenia and improve
functional performance.
Lab Rotation Projects:
A variety of different rotations can be designed based on individual
trainee interests and background. Major efforts at this time include
studies designed to address the role played by inflammatory mediators,
physical stimuli and hormones in regulating the synthesis and release of
pro-inflammatory cytokines such as MIF from bladder cells. We are also
interested in examining the role played by specific cell membrane
receptors (CD74, CD44) and relevant signaling pathways in mediating MIFs
pro-apoptotic in bladder smooth muscle cells, as opposed to its
anti-apoptotic effect in fibroblasts.
Center on
Aging web page
Selected Publications:
Rudolph J.L., Ramlawi B., Kuchel G.A., McElhaney J.E., Xie D., Selke
F.W., Levkoff S.E. and Marcantonio E.R. (2008) Chemokines are Associated
with Delirium after Cardiac Surgery. Journal of Gerontology: Medical
Sciences (In Press)
Leng S.X., McElhaney J.E., Walston J.D., Xie D., Fedarko N.S. and
Kuchel G.A. (2008) ELISA and Multiplex Technologies for Cytokine
Measurement in Inflammation and Aging Research. Journal of Gerontology:
Medical Sciences (In Press)
Pefanco M.A., Kenny, A., Kaplan R, Kuchel G.A., Walsh S., Kleppinger
A. and Prestwood K. (2007) The Effect of 3-year treatment with 0.25 mg/d
of Micronized 17β-Estradiol on Cognitive Function in Older
Postmenopausal Women. Journal of the American Geriatrics Society 55 (3)
426-431.
Inouye S.K., Studenski S., Tinetti M.E. and Kuchel G.A. (2007)
Geriatric syndromes: clinical, research, and policy implications of a
core geriatric concept. Journal of the American Geriatrics Society 55(5)
780-791 (with accompanying editorial by W.B. Hazzard, MD 55(5) 794-796)
Taylor J.A., Kuchel G.A., Hegde P., Voznesensky O.S., Claffey K.,
Tsimikas J., Leng L., Bucala R and Pilbeam C. (2007) Null mutation for
macrophage migration inhibitory factor (MIF) is associated with less
aggressive bladder cancer in mice. BMC Cancer 7(1)135-142.
Estrada M., Kleppinger A., Judge J.O., Walsh S.J and Kuchel G.A.*
(2007) Functional Impact of Relative Versus Absolute Sarcopenia in
Healthy Older Women. Journal of the American Geriatrics Society
55(11)1712-1719.
Taylor J.A., and Kuchel G.A.. (2006). Detrusor Underactivity:
Clinical Features and Pathogenesis of an Underdiagnosed Geriatric
Condition. Journal of the American Geriatrics Society 54 (12) 1920-1932.
Taylor J.A., Zhu Q., Irwin B., Maghayadah Y., Tsimikas J., Pilbeam
C., Leng L., Bucala R. and Kuchel G.A. (2006) Null mutation in
macrophage migration inhibitory factor (MIF) prevents muscle cell loss
and fibrosis in partial bladder outlet obstruction. American Journal of
Physiology - Renal Physiology 291 (6) F1343-1353. |
