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Maria B. Grant, M.D., FARVO

Marilyn Glick Professor of Ophthalmology


Research

The Grant lab is focused on the area of diabetic microvascular complications and stem cell biology. The team has been advancing the field of hematopoietic progenitor biology and the role of progenitors in physiological and pathological vascular repair in the retina for the last 15 years. We showed that healthy self-renewing adult hematopoietic stem cells (HSCs) have functional hemangioblast activity, that is, they can clonally differentiate into all hematopoietic cell lineages as well as endothelial cells that can revascularize the adult retina. Ocular diseases including retinopathy of prematurity (ROP), the leading cause of blindness in the young; diabetic retinopathy (DR), the leading cause of blindness in working age adults; and age-related macular degeneration (AMD), the leading cause of blindness in the elderly  are associated with damaged vascular networks within the retina. Therefore, the ability to repair vascular damage could have a profound impact on these vision threatening conditions.

Endothelial precursor cells (EPC) derived from HSC  play a key role in vascular repair and maintenance, and their function is impeded in diabetes.  We have determined the molecular mechanisms responsible, in part, for this defect as being due to reduced bioavaibility of nitric oxide (NO). We are currently determining ways in which we can pharmacologically/genetically manipulate defective EPCs and restore their natural robust reparative function so as to consider these cells for autologous.

We are also examining the basic mechanisms involved in HSC/EPC homing to areas of hypoxia and their participation in vascular repair. We are particularly interested in understanding the role of hypoxia-regulated factors and we are determining how this process is affected by hyperoxia and hypoxia.  We wish to determine the growth factors and substratum that drive the differentiation of precursors into endothelial cells within retina using immunohistochemistry, enzyme histochemistry, and in situ hybridization. Ultimately our goal is to identify novel factors that can represent potentially therapeutic agents for treatment of ischemic conditions using autologous stem/progenitor cells.

The Grant lab is interested in understanding the pathways of differentiation of HSCs. To this end, we have pre-programmed adult stem cells utilizing cell type-specific genes to confer differentiation specificity and enhance cell-specific repair.  In particular, we expressed a retinal pigment epithelial (RPE) cell-specific transgene in HSC and examined stem cell homing, differentiation and function following RPE injury. We conclude that overexpression of cell-specific genes such as RPE65 and MITF are sufficient to drive differentiation of HSCs, facilitate homing to injured tissue and target repair.  This type of targeted gene expression to force selective differentiation of adult stem cells offers novel therapeutic possibilities for tissue repair throughout the body [Sengupta et al. Mol Ther. 2009 Sep; 17(9):1594-604]

Select the image to see a gallery of slides from the Grant Lab.     grant_ikon.jpg

Current Support

NEI (NIH)
"
LXR as a Novel Therapeutic Target in Diabetic Retinopathy"
We will test the hypothesis that diabetes-induced disruption of the SIRT1-LXR axis results in abnormal lipid metabolism, vascular repair and inflammation. Role: MPI

NIDDK (NIH)
NO Dysregulation of the Peripheral Clock in Diabetic Complications”  
W
e will examine whether in diabetes, a reduction in bioavailable nitric oxide in endothelial cells and bone marrow derived endothelial progenitor cells will cause a diminished amplitude and frequency of the oscillatory pattern of the clock proteins, BMAM1 and PER-2, leading to a loss of circadian regulation of plasminogen activator inhibitor (PAI-1) and subsequent further diminution of nitric oxide levels these cells.  Role: PI

NEI (NIH)
Dysfunction of endothelial precursor subtypes dictates the outcomes of diabetic retinopathy”  
The focus of this grant is to assess the contribution of distinct EPC subpopulations on development of diabetic retinopathy.  Role: PI

NHLBI (NIH)   
Vascular reparative Mechanism by ACE2/Ang-(1-7) in Diabetes”  
The focus of this proposal is to investigate if the balance of vasoprotective axis vs. vasodeleterious axis of the RAS within EPCs can predict progression of microvascular disease in diabetes. Role: MPI

NEI (NIH) 
Bone marrow neuropathy drives retinopathy” 
This proposal examines how loss of innervation (neuronal support) to the bone marrow in diabetes impacts the behavior of bone marrow derived cells, specifically the vascular reparative cells and the monocytes. Role: MPI

NEI  (NIH)       
Dysfunction of Endothelial Precursor Subtypes Dictates the Outcomes of Diabetic Retinopathy”  
This project investigates the role of endothelial progenitor cells in the development of diabetic retinopathy.  Role:  PI

NEI (NIH)         
Circulating Progenitors Determine Angiogenic Outcome in Diabetic Retinopathy”  
This proposal studies the interaction between CD34+endothelial progenitors and angiogenic monocytes CD14+ cells in the pathogenesis of proliferative diabetic retinopathy.  Role:  PI

NHLBI (NIH)        
Angiotensin-Converting Enzyme2 in Vascular Endothelial Function”  
The overall objective of this application is to investigate the role of ACE2 in pulmonary hypertension therapeutics. This application has ~30% overlap with the current application #RC HL099980-1.  Role Co-I

NHLBI (NIH)
CVD Protection Mechanisms involving ACE2/Ang-(1-7) Axis”
The goal of this project is to examine the renin angiotensin system (RAS) in relation to the microvascular complications associated with diabetes. Role: Co-I

NEI (NIH)         
“Non-canonical VEGF receptor signaling regulates retinal neovascularization”   
We will determine how manipulation of the g-secretase complex will reduce vascular permeability and inhibit aberrant retinal and choroidal neovascularization. Role:  Co-I

NEI (NIH)  
“Circadian-dependent autophagy in retinal maintenance and diabetes”  
This project investigates the hypothesis that circadian-regulated autophagy plays a critical role in neurovascular cell homeostasis within the retina and that diabetes alters this circadian rhythmicity leading to dysregulated autophagy and diabetic retinopathy.  Role: Co-I

Beckman Initiative in Macular Research   
“A non- canonical role for β-secretase in AMD”     
We will test the hypothesis that oxidative stress in the RPE increases BACE expression leading to lysosomal dysregulation and reduced mitochondrial function resulting in an AMD-associated phenotype.  Role: Co-I

NIH 
“Optimizing systemic stem/progenitor cell therapy for AMD”  
Successful therapeutic utilization of human or murine HSC requires their programming prior to injection into the systemic circulation, their injection at the time of optimal engraftment potential and preconditioning of the retina by either suppression of resident microglia activation and/or restoring the balance of peripheral pro-inflammatory and homeostatic monocytes.”  Role: MPI

Recent publications from over 170

  1. Bhatwadekar, A.D., Yan, Y., Qi, X., Thinschmidt, J.S., Neu, M.B., Li Calzi, S., Shaw, L.C., Dominiguez, J.M., Busik, J.V., Lee, C., Boulton, M.E., Grant, M.B., 2013. Per2 mutation recapitulates the vascular phenotype of diabetes in the retina and bone marrow. Diabetes 62, 273-282.
  2. Caballero, S., Hazra, S., Bhatwadekar, A., Li Calzi, S., Paradiso, L.J., Miller, L.P., Chang, L.J., Kern, T.S., Grant, M.B., 2013. Circulating mononuclear progenitor cells: differential roles for subpopulations in repair of retinal vascular injury. Investigative ophthalmology & visual science 54, 3000-3009.
  3. Choi, J., Lin, A., Shrier, E., Lau, L.F., Grant, M.B., Chaqour, B., 2013. Degradome products of the matricellular protein CCN1 as modulators of pathological angiogenesis in the retina. The Journal of biological chemistry 288, 23075-23089.
  4. Hazra, S., Jarajapu, Y.P., Stepps, V., Caballero, S., Thinschmidt, J.S., Sautina, L., Bengtsson, N., Licalzi, S., Dominguez, J., Kern, T.S., Segal, M.S., Ash, J.D., Saban, D.R., Bartelmez, S.H., Grant, M.B., 2013. Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia 56, 644-653.
  5. Hazra, S., Stepps, V., Bhatwadekar, A.D., Caballero, S., Boulton, M.E., Higgins, P.J., Nikonova, E.V., Pepine, C.J., Thut, C., Finney, E.M., Stone, D.J., Bartelmez, S.H., Grant, M.B., 2013. Enhancing the Function of CD34(+) Cells by Targeting Plasminogen Activator Inhibitor-1. PloS one 8, e79067.
  6. Hu, P., Thinschmidt, J.S., Yan, Y., Hazra, S., Bhatwadekar, A., Caballero, S., Salazar, T., Miyan, J.A., Li, W., Derbenev, A., Zsombok, A., Tikhonenko, M., Dominguez, J.M., 2nd, McGorray, S.P., Saban, D.R., Boulton, M.E., Busik, J.V., Raizada, M.K., Chan-Ling, T., Grant, M.B., 2013. CNS inflammation and bone marrow neuropathy in type 1 diabetes. The American journal of pathology 183, 1608-1620.
  7. Jarajapu, Y.P., Bhatwadekar, A.D., Caballero, S., Hazra, S., Shenoy, V., Medina, R., Kent, D., Stitt, A.W., Thut, C., Finney, E.M., Raizada, M.K., Grant, M.B., 2013. Activation of the ACE2/angiotensin-(1-7)/Mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors. Diabetes 62, 1258-1269.
  8. Liu, L., Qi, X., Chen, Z., Shaw, L., Cai, J., Smith, L.H., Grant, M.B., Boulton, M.E., 2013. Targeting the IRE1alpha/XBP1 and ATF6 arms of the unfolded protein response enhances VEGF blockade to prevent retinal and choroidal neovascularization. The American journal of pathology 182, 1412-1424.
  9. Nguyen, D.V., Li Calzi, S., Shaw, L.C., Kielczewski, J.L., Korah, H.E., Grant, M.B., 2013. An ocular view of the IGF-IGFBP system. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 23, 45-52.
  10. Shenoy, V., Gjymishka, A., Jarajapu, Y.P., Qi, Y., Afzal, A., Rigatto, K., Ferreira, A.J., Fraga-Silva, R.A., Kearns, P., Douglas, J.Y., Agarwal, D., Mubarak, K.K., Bradford, C., Kennedy, W.R., Jun, J.Y., Rathinasabapathy, A., Bruce, E., Gupta, D., Cardounel, A.J., Mocco, J., Patel, J.M., Francis, J., Grant, M.B., Katovich, M.J., Raizada, M.K., 2013. Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. American journal of respiratory and critical care medicine 187, 648-657.
  11. Tikhonenko, M., Lydic, T.A., Opreanu, M., Li Calzi, S., Bozack, S., McSorley, K.M., Sochacki, A.L., Faber, M.S., Hazra, S., Duclos, S., Guberski, D., Reid, G.E., Grant, M.B., Busik, J.V., 2013. N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PloS one 8, e55177.
  12. Yan, Y., Salazar, T.E., Dominguez, J.M., 2nd, Nguyen, D.V., Li Calzi, S., Bhatwadekar, A.D., Qi, X., Busik, J.V., Boulton, M.E., Grant, M.B., 2013. Dicer Expression Exhibits a Tissue-Specific Diurnal Pattern That Is Lost during Aging and in Diabetes. PloS one 8, e80029.
  13. Cai, J., Qi, X., Kociok, N., Skosyrski, S., Emilio, A., Ruan, Q., Han, S., Liu, L., Chen, Z., Bowes Rickman, C., Golde, T., Grant, M.B., Saftig, P., Serneels, L., de Strooper, B., Joussen, A.M., Boulton, M.E., 2012. beta-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO molecular medicine 4, 980-991.
  14. Chintala, H., Liu, H., Parmar, R., Kamalska, M., Kim, Y.J., Lovett, D., Grant, M.B., Chaqour, B., 2012. Connective tissue growth factor regulates retinal neovascularization through p53 protein-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene. The Journal of biological chemistry 287, 40570-40585.
  15. Hazra, S., Rasheed, A., Bhatwadekar, A., Wang, X., Shaw, L.C., Patel, M., Caballero, S., Magomedova, L., Solis, N., Yan, Y., Wang, W., Thinschmidt, J.S., Verma, A., Li, Q., Levi, M., Cummins, C.L., Grant, M.B., 2012. Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes. Diabetes 61, 3270-3279.
  16. Jadhao, C.S., Bhatwadekar, A.D., Jiang, Y., Boulton, M.E., Steinle, J.J., Grant, M.B., 2012. Nerve growth factor promotes endothelial progenitor cell-mediated angiogenic responses. Investigative ophthalmology & visual science 53, 2030-2037.
  17. Jarajapu, Y.P., Cai, J., Yan, Y., Li Calzi, S., Kielczewski, J.L., Hu, P., Shaw, L.C., Firth, S.M., Chan-Ling, T., Boulton, M.E., Baxter, R.C., Grant, M.B., 2012. Protection of blood retinal barrier and systemic vasculature by insulin-like growth factor binding protein-3. PloS one 7, e39398.
  18. Jun, J.Y., Zubcevic, J., Qi, Y., Afzal, A., Carvajal, J.M., Thinschmidt, J.S., Grant, M.B., Mocco, J., Raizada, M.K., 2012. Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. Hypertension 60, 1316-1323.
  19. Li, N., Ma, L., Liu, X., Shaw, L., Li Calzi, S., Grant, M.B., Neu, J., 2012. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuates hyperoxia-induced small intestinal injury in neonatal mice. Journal of pediatric gastroenterology and nutrition 54, 499-504.
  20. Ma, L., Li, N., Liu, X., Shaw, L., Li Calzi, S., Grant, M.B., Neu, J., 2012. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice. Nutrition 28, 1186-1191.
  21. Mitter, S.K., Rao, H.V., Qi, X., Cai, J., Sugrue, A., Dunn, W.A., Jr., Grant, M.B., Boulton, M.E., 2012. Autophagy in the retina: a potential role in age-related macular degeneration. Advances in experimental medicine and biology 723, 83-90.
  22. Nguyen, D.V., Shaw, L.C., Grant, M.B., 2012. Inflammation in the pathogenesis of microvascular complications in diabetes. Frontiers in endocrinology 3, 170.
  23. Park, S.S., Caballero, S., Bauer, G., Shibata, B., Roth, A., Fitzgerald, P.G., Forward, K.I., Zhou, P., McGee, J., Telander, D.G., Grant, M.B., Nolta, J.A., 2012. Long-term effects of intravitreal injection of GMP-grade bone-marrow-derived CD34+ cells in NOD-SCID mice with acute ischemia-reperfusion injury. Investigative ophthalmology & visual science 53, 986-994.
  24. Patel, V.B., Bodiga, S., Basu, R., Das, S.K., Wang, W., Wang, Z., Lo, J., Grant, M.B., Zhong, J., Kassiri, Z., Oudit, G.Y., 2012. Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis. Circulation research 110, 1322-1335.
  25. Qi, X., Cai, J., Ruan, Q., Liu, L., Boye, S.L., Chen, Z., Hauswirth, W.W., Ryals, R.C., Shaw, L., Caballero, S., Grant, M.B., Boulton, M.E., 2012. gamma-Secretase inhibition of murine choroidal neovascularization is associated with reduction of superoxide and proinflammatory cytokines. Investigative ophthalmology & visual science 53, 574-585.
  26. Segal, M.S., Sautina, L., Li, S., Diao, Y., Agoulnik, A.I., Kielczewski, J., McGuane, J.T., Grant, M.B., Conrad, K.P., 2012. Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice. Blood 119, 629-636.
  27. Yellowlees Douglas, J., Bhatwadekar, A.D., Li Calzi, S., Shaw, L.C., Carnegie, D., Caballero, S., Li, Q., Stitt, A.W., Raizada, M.K., Grant, M.B., 2012. Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy. Progress in retinal and eye research 31, 481-494.

 

B.S. - University of Florida, Gainesville, FL, 1976  Chemistry

M.D. - University of Florida, Gainesville, FL  1979  Medicine

Resident - University of Florida, Gainesville, FL  1979-1982  Internal Medicine

Fellow - University of Florida, Gainesville, FL  1982-1984  Endocrinology and Metabolism


At Indiana University

Lynn Shaw
Senior Research Scientist
Ph.D., University of Texas at Dallas, Richardson, Texas

Sergio Li Calzi
Senior Research Scientist
Ph.D., Medical College of Ohio, Toledo, Ohio

Eleni Beli
Postdoctoral Fellow
Ph.D., Michigan State University, East Lansing, Michigan

Hu, Ping
Postdoctoral Fellow
Ph.D. University of Sydney, Sydney, Australia

Tatiana Salazar
Graduate Student
Bc.S., University of Costa Rica, Mercedes, Costa Rica

James Dominguez II
Graduate Student

At University of Florida

Sergio Caballero, Jr.
Senior Biological Scientist
M.S., University of Florida, Gainesville, Florida

Jeffery Thinschmidt
Biological Scientist
M.S., Miami University, Oxford, OH.

Amy Davis
Project Coordinator

Other Experience and Professional Memberships

1983-present                 Member, American Diabetes Association 

1983-present                 Member, The Endocrine Society

1996-present                 Ad-hoc Member for NIH-NIDDK, NEI, AHA study section, JDRF Review complications

2002-2005                     JDRF Medical Science Review Committee, Member of Complications Section

2002-2006                     NIH-HM study section, Regular Member

2004-2008                     NIH-BDPE study section permanent member

2008-present                  Editorial Board IOVS

2009-present                  Fellow of the Association Research in Vision and Ophthalmology

 

Honors

1989                               Mary Jane Kugel Award JDRF International 

2003                               University of Florida, College of Medicine, Faculty Research Prize, Basic Science

2013                               University of Florida, College of Medicine, Graduate Student Mentoring Award 

 

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