The Chemokine System in Collateral Artery Formation

  • Shireman, Paula K (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
My goal is to be an academic vascular surgeon who has an independent research
laboratory and teaches vascular surgery in a university setting. In this
proposal, I have identified expert mentors and outlined a course of study
which should strengthen my research skills, particularly in the area of
immunology. My research goal is to understand the basic mechanisms of
collateral artery formation. Formation of collateral arteries to naturally
"bypass" arterial obstructions from atherosclerosis occurs in all patients,
but to a variable degree. Understanding the mechanisms of collateral artery
formation could lead to new primary and adjuvant treatments for
atherosclerosis. My long-range goal is to understand the influence of the
chemokine system in collateral artery formation. Central to our hypothesis is
that the chemokine system influences the in vivo temporal and spatial pattern
of the inflammatory/immune response following acute vascular occlusion. We
hypothesize that 1) chemokines with different chemoattractant properties will
affect the quantity and character of the inflammatory infiltrate as well as
local cytokine/chemokine profiles after vascular occlusion and 2) monocyte
recruitment is an important determinant of collateral artery formation. To
test our hypothesis, we have in preliminary studies developed a mouse hind
limb model of ischemia and demonstrated that local infusion of MCPA at the
site of arterial occlusion is associated with an increase in blood flow as
compared to normal saline infusion. We have also shown that inflammatory
cells are attracted to the ischemic leg, as compared to the normal, non-excised
control leg. To determine the relationship between vascular
remodeling, chemokine system and the nature of the immune/inflammatory cells
recruited after vascular occlusion, we have proposed two specific aims. In
the specific aim #1, we will alter the inflammatory infiltrate by infusing
chemokines with different chemoattractant properties: specific for monocytes,
neutrophils and lymphocytes to determine the effect of this altered immune
response on collateral artery formation. In the second specific aim, we will
determine the influence of monocytes on collateral artery formation using mice
that have severely impaired monocyte recruitment, i.e. mice lacking the CC
chemokine receptor 2 (CCR2) and its ligand, MCPA. The experiments outlined in
this proposal are innovative because they employ the use of our mouse hind
limb ischemia model and utilize the power of genetic knockouts. The
significance of the research is that a better understanding of the mechanisms
of collateral artery formation could lead to the design of novel primary or
adjuvant treatments for atherosclerotic occlusive disease and thereby decrease
death and disability rates from myocardial infarction and amputations. These
investigations, under the guidance of my mentors and coupled with the courses
and seminars in this proposal will substantially broaden my scientific
experience to allow me to become an independent scientist.
StatusFinished
Effective start/end date7/15/026/30/07

Funding

  • National Institutes of Health: $129,060.00
  • National Institutes of Health: $129,060.00
  • National Institutes of Health: $129,060.00
  • National Institutes of Health: $129,060.00
  • National Institutes of Health: $129,060.00

ASJC

  • Medicine(all)

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