Thomas Coffman

Personal Information
Title Professor
Expertise Nephropathy
Institution Duke University Medical Center
Data Summary
TypeCount
Grants/SubContracts 2
Progress Reports 10
Presentations 8
Publications 16
Protocols 0
Committees 2
Experiments 0
Strains 13
Models 6

Angiogenic Signals in Diabetic Complications
Grant Number: DK076136

Abstract: In humans with diabetes, abnormal angiogenesis contributes to the development of end-organ damage. In this regard, "excessive" angiogenesis and increased activity of the vascular endothelial growth factor (VEGF) signaling pathway have been associated with diabetic complications such as retinopathy. In contrast, an inadequate angiogenesis response with a reduced capacity to promote collateral blood vessel growth in cardiac and particularly peripheral skeletal muscle result in more severe manifestations of vascular disease in diabetes. However, the mechanisms responsible for the loss of control of angiogenesis in diabetes and how this dysregulation modulates tissue pathology are not clear. We hypothesize that abnormal signaling in VEGF-associated pathways is a critical factor in the pathogenesis of diabetic complications including peripheral artery disease (PAD) and nephropathy. Furthermore, we posit that distinct properties of individual tissues determine the effects of diabetes on the local angiogenesis response, shaping the resulting pathology. Accordingly, to develop better models of diabetic PAD and nephropathy, we will generate mouse lines with inducible alterations of angiogenic signaling pathways targeted to specific cell lineages in blood vessels, skeletal muscle and kidney. Because both enhanced and diminished VEGF activities have independently been associated with diabetic complications, we will produce models with up- or down-regulated angiogenic signaling. The long-term goals of our studies are: (1) To understand how alterations in angiogenic factors contribute to the development of diabetic complications and (2) To develop mouse models of diabetic PAD and nephropathy that more faithfully reproduce the respective human conditions. To achieve these goals we propose the following specific aims: 1. To develop mouse models with genetic modifications of key signaling pathways linked to angiogenesis. 2. To determine the effects of diabetes on angiogenic signaling in a well-established model of peripheral artery disease. 3. To define the consequences of altered angiogenic signaling on the development of albuminuria and nephropathy in diabetes.


Institution: Duke University Medical Center
2301 Erwin Road
Durham, NC
Fiscal Year:2006
Department:MEDICINE
Project Start: 9/30/2006
Project End: 8/31/2011
ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

SubContract(s)


Immune Mechanisms in Diabetic Nephropathy
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the US and in many developed countries around the world. Nonetheless, understanding of the pathogenesis of DN is limited and there is a significant unmet need for new, specific therapies to prevent or reverse kidney damage in DN. Our laboratory has developed a mouse model, combining type 1 diabetes with chronic, low-grade activation of the renin-angiotensin system (RAS), which recapitulates key features of human DN including. In microarray studies of glomerular mRNA, we have found that the development of DN is this mouse line is associated with broad up-regulation of gene expression patterns associated with immune activation and inflammation. Moreover, we find discordant mRNA signatures between mouse strains that are susceptible (S) or resistant (R) to DN, with activation of immune and inflammatory pathways in the S strain and broad suppression of these pathways in the R strain. Accordingly, we hypothesize that activation of the immune system is a key determinant of susceptibility to DN. RAS activation, which is critical for the development of DN in humans and in this mouse model, has powerful immunomodulatory effects. Therefore, we suggest that stimulation of adaptive and/or innate immune responses in DN is facilitated by angiotensin II acting via type 1 angiotensin (AT1) receptors in specific populations of immune and inflammatory cells. Although a role for inflammatory mechanisms in diabetic complications has been suggested previously, the specific contribution of inflammation to DN and the molecular triggers for immune activation in this setting are not clear. We will explore these issues using unique mouse lines developed in our laboratory through the following Specific Aims: 1. Define the role of T cell activation by angiotensin II in the development of DN; 2. Determine whether modulation of macrophage function by the RAS influences the pathogenesis of DN. We anticipate that these studies will provide new insights into the role of immune and inflammatory pathways in the pathogenesis of DN. Furthermore, they will define the capacity for cross-talk between the RAS and the immune system to modulate the severity of diabetic complications.


Progress Reports

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Immune Mechanisms in Diabetic Nephropathy (Coffman, Thomas)
12/11/2015View Progress Report Document
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Annual Reports

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Coffman, Thomas (1/2004)
2004Annual Report
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Coffman, Thomas (2004)
2004Annual Report
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Coffman, Thomas (2005)
2005Annual Report
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Coffman, Thomas (2006)
2006Annual Report
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Coffman, Thomas (2007)
2007Annual Report
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Coffman, Thomas (2008)
2008Annual Report
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Coffman, Thomas (2009)
2009Annual Report
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Coffman, Thomas (2010)
2010Annual Report
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Coffman, Thomas (2011)
2011Annual Report
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 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2017; Items: 1

 
Modelling diabetic nephropathy in mice.
Azushima K, Gurley SB, Coffman TM
Nature reviews. Nephrology, 2017
29062142
Published

Year: 2013; Items: 2

 
Diabetic Nephropathy: A National Dialogue.
Breyer MD, Coffman TM, Flessner MF, Fried LF, Harris RC, Ketchum CJ, Kretzler M, Nelson RG, Sedor JR, Susztak K, on behalf of the Kidney Research National Dialogue (KRND)
Clinical journal of the American Society of Nephrology : CJASN, 2013
23788618
Published
 
The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice.
Dolber PC, Jin H, Nassar R, Coffman TM, Gurley SB, Fraser MO
Neurourology and urodynamics, 2013
25048174
Published

Year: 2010; Items: 2

 
Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice.
Gurley SB, Mach CL, Stegbauer J, Yang J, Snow KP, Hu A, Meyer TW, Coffman TM
American journal of physiology. Renal physiology, 2010 (298(3)), F788 - F795
20042456
Published
 
20889121
Published

Year: 2009; Items: 2

 
Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.
Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM
Hypertension, 2009 (54(3)), 652 - 658
19652084
Published
 
Mouse Models of Diabetic Nephropathy: A Midstream Analysis from the Diabetic Complications Consortium
Frank C. Brosius IIIa, Charles E. Alpersb, Erwin P. Bottingerc, Matthew D. Breyerd, ThomasM. Coffmane, Susan B. Gurleye, Raymond C. Harrisf, Masao Kakokig, Matthias Kretzler, Edward H. Leiterh, Moshe Levii, Richard A. McIndoej, Kumar Sharmak, Oliver Smithiesg, Katalin Susztakl, Nobuyuki Takahashig, Takamune Takahashif
Journal of the American Society of Nephrology : JASN, 2009 (20(12)), 2503 - 2512
19729434
Published

Year: 2008; Items: 3

 
High cholesterol feeding in C57/Blc6 mice alters expression within the VEGF receptor-ligand family in corporal tissue.
Xie D, Hazarika S, Andrich AJ, Padgett ME, Kontos CD, Donatucci CF, Annex BH
The journal of sexual medicine, 2008 (5), 1137 - 1148
18439153
Published
 
The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching.
Kappas NC, Zeng G, Chappell JC, Kearney JB, Hazarika S, Kallianos KG, Patterson C, Annex BH, Bautch VL
The Journal of cell biology, 2008 (181), 847 - 858
18504303
Published
 
Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.
Hazarika S, Angelo M, Li Y, Aldrich AJ, Odronic SI, Yan Z, Stamler JS, Annex BH
Arteriosclerosis, thrombosis, and vascular biology, 2008 (28(12)), 2144 - 2150
18818418
Published

Year: 2007; Items: 3

 
Toward a Mouse Model of Diabetic Nephropathy: Is Endothelial Nitric Oxide Synthase the Missing Link?
Quagin, SE Coffman, TM
Journal of the American Society of Nephrology : JASN, 2007 (18), 364 - 366
17259594
Published
 
The renin-angiotensin system and diabetic nephropathy.
Gurley SB, Coffman TM
Seminars in nephrology, 2007 (27), 144 - 152
17418683
Published
 
Impaired Angiogenesis Following Hind-Limb Ischemia in Type 2 Diabetes Mellitus: Differential Regulation of VEGFR1, R2, and Soluble VEGFR-1
Surovi Hazarika, MD, PhD; Ayotunde O Dokun, MD, PhD; Younjun Li, MD; Aleksander S. Popel MS, PhD; Christopher D. Kontos, MD; Brian H. Annex, MD
Circulation research, 2007 (101(9)), 948 - 956
17823371
Published

Year: 2006; Items: 1

 
Impact of Genetic Background on Nephropathy in Diabetic Mice
Susan B. Gurley, Sharon E. Clare, Kamie P. Snow, Timothy W. Meyer, and Thomas M. Coffman
American journal of physiology. Renal physiology, 2006 (290), F214 - F222
16118394
Published

Year: 2005; Items: 2

 
Mouse Models of Diabetic Nephropathy
MATTHEW D. BREYER, ERWIN BÖTTINGER, FRANK C. BROSIUS, III, THOMAS M. COFFMAN, RAYMOND C. HARRIS, CHARLES W. HEILIG, AND KUMAR SHARMA (FOR THE AMDCC)
Journal of the American Society of Nephrology : JASN, 2005 (16), 27 - 45
15563560
Published
 
Diabetic nephropathy: of mice and men.
Breyer MD, Böttinger E, Brosius FC, Coffman TM, Fogo A, Harris RC, Heilig CW, Sharma K
Advances in chronic kidney disease, 2005 (12(2)), 128 - 145
15822049
Published

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Title YearTypeOptions
Annex, Brian (2009)
2009Presentation
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Coffman, Thomas (10/17/2005)
2005Presentation
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Coffman, Thomas (2003)
2003Presentation
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Coffman, Thomas (2004)
2004Presentation
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Coffman, Thomas (2006)
2006Presentation
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Coffman, Thomas (2009)
2009Presentation
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Coffman, Thomas (3/23/2005)
2005Presentation
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K) Genetics/Epigentics Workgroup
2010Presentation
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No protocols found.

No experiments found.