While transplantation can be lifesaving, chronic rejection is frequently a major obstacle to long-term graft survival. Microvascular destruction is critical root-cause underlying this life-threatening process. Current immunosuppressive regimens do not sufficiently protect against microvascular injury and are not designed to help restore the transplant with healthy vascular cells. Promoting microvascular repair during rejection episodes is a promising new avenue for preventing chronic rejection in solid organ recipients. An understanding of the basic mechanisms explaining adaptive cell replacement is now needed to move the field forward. The proposed studies of this competitive renewal R01 grant are designed to explain two major processes: 1) how recipient cells are recruited to replace damaged transplant endothelial cells in microvessels and 2) how particular recipient cells, called Tie2 monocytes (TEMs), are also recruited to facilitate the angiogenic process. The project focuses on the role of the hypoxia-inducible factors (HIFs) that are the key transcription factors responsive to low tissue oxygen during rejection episodes when injured microvessels stop perfusing the transplanted tissues and fibrotic remodeling is promoted.
Specific Aim 1 will determine how recipient cells, responding to HIF signals, differentially participate in transplant microvascular repair. The first subaim evaluates the contribution of endothelial-lineage cells and how a gain- and loss-of-function of HIF-1a or HIF-2a affects recipient cells investing into microvessels. The second subaim evaluates the contribution of non-endothelial cells, such as mesenchymal stem cells, and similarly evaluates how HIF-1a expression affects their ability to incorporate into damaged vessels.
Specific Aim 2 will determine the role of HIF-1a and HIF-2a on TEM migration and angiogenesis. Four subaims evaluate the role of HIF isoforms in a series of in vivo and in vitro studies that address whether upregulating HIF production in TEMs promotes angiogenesis via the production of prostaglandin E2.

Public Health Relevance

Transplantation is the only treatment available for a number of advanced diseases but is limited by a high rate of organ failure. Emerging evidence has strongly implicated damage to the small blood vessels supplying transplant tissue as being a key reason for these poor outcomes. This grant focuses on how cells from the transplant recipient can be recruited to repair damaged blood vessels and restore organ health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095686-07
Application #
9231472
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Xiao, Lei
Project Start
2009-04-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
7
Fiscal Year
2017
Total Cost
$349,265
Indirect Cost
$92,382
Name
Palo Alto Veterans Institute for Research
Department
Type
Research Institutes
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Hsu, Joe L; Manouvakhova, Olga V; Clemons, Karl V et al. (2018) Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation. Sci Transl Med 10:
Jiang, Xinguo; Tian, Wen; Tu, Allen B et al. (2018) Endothelial HIF-2? is Required for the Maintenance of Airway Microvasculature. Circulation :
Lin, Y-C; Sung, Y K; Jiang, X et al. (2017) Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. Am J Transplant 17:1229-1241
Pasupneti, S; Manouvakhova, O; Nicolls, M R et al. (2017) Aspergillus-related pulmonary diseases in lung transplantation. Med Mycol 55:96-102
Lama, Vibha N; Belperio, John A; Christie, Jason D et al. (2017) Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight 2:
Zamora, Martin R; Martinu, Tereza; Nicolls, Mark R (2017) Introduction to the 59th Annual Thomas L. Petty Aspen Lung Conference. Lung Transplantation: Opportunities for Repair and Regeneration. Ann Am Thorac Soc 14:S209
Nicolls, Mark R; Dhillon, Gundeep S; Daddi, Niccolò (2016) A Critical Role for Airway Microvessels in Lung Transplantation. Am J Respir Crit Care Med 193:479-81
Mooney, J J; Hedlin, H; Mohabir, P K et al. (2016) Lung Quality and Utilization in Controlled Donation After Circulatory Determination of Death Within the United States. Am J Transplant 16:1207-15
Nicolls, Mark R; Hsu, Joe L; Jiang, Xinguo (2016) Microvascular injury after lung transplantation. Curr Opin Organ Transplant 21:279-84
Jothimuthu, Preetha; Hsu, Joe L; Chen, Robert et al. (2016) Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip. ChemNanoMat 2:904-910

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