? ? My immediate career objectives are to develop a reputation for high quality research and to train graduate and postdoctoral students in the cardiovascular and lymphatic research field. My long-term career are to advance the level of understanding the regulatory mechanisms of lymphatic muscle contractility under normal and diseased/pathophysiological conditions. Lymphatic muscle exhibits strong/phasic contractions, much higher shortening velocities and different intracellular calcium dynamics. Unfortunately little information is known about the molecular mechanisms that are responsible for these unique characteristics. In this proposal we will use the available contractile protein gene knock out models or transgenic models with overexpression of contractile protein isoforms to test the central hypothesis remodeling of thick or thin filament proteins in the contractile apparatus of lymphatic muscle modulates its contractile dynamics through altering the calcium sensitivity and crossbridge activation mechanisms.
The specific aims are: (1) To determine the functional roles of SM-B myosin heavy chain (MHC) in the phasic and tonic contraction of lymphatics, (2) To define the roles of tropomyosin in the thin filament-mediated contraction of lymphatics. We will use SM-B MHC knockout and SM-MHC/calponin double knockout mouse models. The vascular smooth muscle a-actin promoter will be to express striated muscle tropomyosin in lymphatic muscle. An adenoviral siRNA approach will be used knock down the smooth muscle a- and p-TM gene expression in lymphatics. We will isolated/cannulated vessels from iliac and thoracic duct lymphatics to study the contractile characteristics of lymphatics. Force and calcium measurements will be conducted in the lymphatic segment preparations (both intact and skinned) to determine the calcium sensitivity and cooperativity mechanisms of lymphatics. The contractile mechanisms of lymphatics are poorly understood and this study will significantly advance our knowledge of the basis for the lymphatic vessel function. These studies further advance my training lymphatic research using mouse models, which would allow me to develop and use genomic proteomic approaches to determine the signaling pathways that regulate lymphatic muscle function. ? (End of Abstract) ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02HL086650-02
Application #
7485678
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Commarato, Michael
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$100,429
Indirect Cost
Name
Texas A&M University
Department
Physiology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Dougherty, Patrick J; Nepiyushchikh, Zhanna V; Chakraborty, Sanjukta et al. (2014) PKC activation increases Ca²? sensitivity of permeabilized lymphatic muscle via myosin light chain 20 phosphorylation-dependent and -independent mechanisms. Am J Physiol Heart Circ Physiol 306:H674-83
Tangney, Jared R; Chuang, Joyce S; Janssen, Matthew S et al. (2013) Novel role for vinculin in ventricular myocyte mechanics and dysfunction. Biophys J 104:1623-33
Chakraborty, Sanjukta; Gurusamy, Manokaran; Zawieja, David C et al. (2013) Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis. Microcirculation 20:349-64
Mamidi, Ranganath; Muthuchamy, Mariappan; Chandra, Murali (2013) Instability in the central region of tropomyosin modulates the function of its overlapping ends. Biophys J 105:2104-13
Zawieja, Scott D; Wang, Wei; Wu, Xin et al. (2012) Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome. Am J Physiol Heart Circ Physiol 302:H643-53
Gashev, Anatoliy A; Li, Jieli; Muthuchamy, Mariappan et al. (2012) Adenovirus-mediated gene transfection in the isolated lymphatic vessels. Methods Mol Biol 843:199-204
Chakraborty, Sanjukta; Nepiyushchikh, Zhanna; Davis, Michael J et al. (2011) Substance P activates both contractile and inflammatory pathways in lymphatics through the neurokinin receptors NK1R and NK3R. Microcirculation 18:24-35
Nepiyushchikh, Zhanna V; Chakraborty, Sanjukta; Wang, Wei et al. (2011) Differential effects of myosin light chain kinase inhibition on contractility, force development and myosin light chain 20 phosphorylation of rat cervical and thoracic duct lymphatics. J Physiol 589:5415-29
Wu, Xin; Chakraborty, Sanjukta; Heaps, Cristine L et al. (2011) Fibronectin increases the force production of mouse papillary muscles via ýý5ýý1 integrin. J Mol Cell Cardiol 50:203-13
Sarin, Vandana; Muthuchamy, Mariappan; Heaps, Cristine L (2011) Ca²? sensitization of cardiac myofilament proteins contributes to exercise training-enhanced myocardial function in a porcine model of chronic occlusion. Am J Physiol Heart Circ Physiol 301:H1579-87

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