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 (UConn Health Center 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.
Selected Publications
Taylor J.A., Ristau B., Bonnemaison M., Voznesensky O.S., Hegde
P., Kuchel G.A. and Pilbeam C.C. (2009) Regulation of the
Prostaglandin Pathway during Development of Invasive Bladder
Cancer in Mice. Prostaglandins and Other Lipid Mediators 88:
36-41.
Taylor J.A. and Kuchel G.A. (2009) The Clinical and Research
Implications of Bladder Cancer in the Elderly. Nature (Clinical
Practice Urology) 6.
Kuchel G.A., Moscufo N., Guttmann C., Zeevi N., Wakefield D.,
Schmidt J., DuBeau C. and Wolfson L. (2009) Localization of
Brain White Matter Hyperintensities and Urinary Incontinence in
Community-Dwelling Older Adults. Journal of Gerontology: Medical
Sciences (In Press)
Kuchel G.A.. (2009) Aging and Homeostatic Regulation. Ch. 51.
IN Hazzard’s Principles of Geriatric Medicine and Gerontology.
(Eds. Halter J.B., Hazzard W., Ouslander J.G., Tinetti M.,
Woolard N., Studenski S., High K. and Asthana S.) 6th edition.
McGraw-Hill, New York, NY.
Smith P.P. and Kuchel G.A. (2009) Aging of the Urinary Tract.
Chapter 18 IN Brocklehurst's Textbook of Geriatric Medicine and
Gerontology. 7th edition. Elsevier, Philadelphia, PA (In Press)
Aviv A., Gardner S., Kuchel G.A., Kummerfeld S., Love C.L.,
Vlassara H., White M. and Colins A. (2008) Inflammation’s
Effects on Aging IN The Future of the Human Healthspan.
Demography, Evolution, Medicine and Bioengineering. Task Group
Summaries. The National Academies. Keck Futures Initiative. The
National Academies Press. Washington, DC.
DuBeau C.E., Harari D., Johnson T., Kuchel G.A., Palmer M.,
Pfisterer M. and Wagg A. Incontinence in The Frail Elderly. IN
Incontinence. 4th International Consultation on Incontinence.
July 4-7, 2008. Editions 21, Paris, France (In Press)
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.
rev. 2/09 |
