Neural and Endocrine Regeneration

Teri Belecky-Adams
Ellen A.G. Chernoff, PhD
Linda DiMeglio, MD, MPH
James A. Marrs, PhD
Mark Pescovitz, MD
Simon J. Rhodes, PhD
Randall J. Roper, PhD
John H. Schild, PhD
Feng C. Zhou, PhD

Teri Belecky-Adams

Position

• Assistant Professor

Address
Department of Biology
School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St.
Indianapolis, IN 46202

Phone: (317) 278-5715
Fax: (317) 274-2846
Email: tbadams@iupui.edu

Research Interests

Development of a functional eye involves two basic processes. First, a homogeneous undifferentiated population of cells must be induced to acquire specific cell fates. Second, cells must also have a sense of where they lie within the retina (a process known as patterning) in order to form proper topographical connections with the rest of the brain. A loss of either one of these processes can lead to a loss of vision. My lab is focused on understanding the roles of a large family of proteins, known as the TGF-Beta family of growth factors, in the differentiation and patterning of the vertebrate eye. We are using tools such as microinjection of retroviruses carrying transgenes into the developing eye, as well as addition of factors in vitro to retinal cultures to perturb growth factor signaling to assay effects on differentiation as well as axonal and dendritic outgrowth. By understanding the mechanisms whereby cells differentiate and form connections, we will one day be able to understand and apply this knowledge to eradicate congenital defects and treat injured or degenerating neurons.

Recent Publications

• Sehgal, R, Andres, D, Adler, R, and Belecky-Adams, TL (2006) Bone Morphogenetic Protein 7 Increases Chick Photoreceptor Outer Segment Initiation. Invest Ophthalmol Vis Sci. 47:3625-34.
• Fong, SL, Criswell, MH, Belecky-Adams, T, Fong, WB, McClintick, JN, Kap, WW, and Edenberg, HJ (2005) Characterization of a transgenic mouse line lacking photoreceptor development within the ventral retina. Exp Eye Res. 2005 Oct;81(4):376-88.
• Belecky-Adams, T.L. Michael Holmes, Yuqing Shan, C. Susan Tedesco, Carla Mascari, Ajay Kaul, David C. Wight, Randal E. Morris, Mark Sussman, Jack Diamond, Linda M. Parysek (2003) An Intact Intermediate Filament Network is Required for Collateral Sprouting of Small Diameter Nerve Fibers. J. Neurosci. 23, 9312-9319.
• Adler, R. and Belecky-Adams, T. L. (2002). The role of bone morphogenetic proteins in the differentiation of the ventral optic cup. Development 129, 3161-71.
• Belecky-Adams, T., Adler, R. and Beebe, D. (2002). Bone morphogenetic protein signaling and the initiation of lens fiber cell differentiation. Development 129, 3795-802.

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Ellen A.G. Chernoff, PhD

Positions

• Associate Professor of Biology, IUPUI
• Adjuct faculty Stark Institute for Neuroscience, IUSM

Address
Dept. of Biology
School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St.
Indianapolis, IN 46202-5132

Phone: (317) 274-0591
Fax: (317) 274-2846
E-mail: echernof@iupui.edu

Research Interests

My laboratory studies amphibian spinal cord and limb regeneration. We examine spinal cord and limb regeneration using the frog Xenopus laevis, and a salamander, the axolotl (Ambystoma mexicanum). Projects include characterizing the stem cell properties of spinal cord and expression of dorsoventral patterning genes in regeneration. We also study the involvement of stem cells in amphibian limb regeneration as an alternative to the involvement of dedifferentiation in this process. We are comparing differences at different stages of the life cycle. Frog tadpoles lose their ability to regenerate as they approach metamorphosis, and we compare regenerating and non-regenerating tissue. Salamanders regenerate even as adults, so we can compare regeneration in larval, juvenile and adult animals. Lastly, we are comparing the role of stem cells in regeneration between normal axolotls and the mutant short-toes (s/s) which can regenerate spinal cord and tail, but not limbs.

Recent Publications

• Chernoff EAG, Sato K, Corn A and Karcavich RE (2002) Spinal Cord Regeneration: Intrinsic Properties and Emerging Mechanisms. Sem Cell Develop Biol 13:361-368
• Nye HL, Cameron J, Chernoff EAG and Stocum DL. (2003) Regeneration of the Urodele Limb: A Review. Develop. Dyn. 226:280-294.
• Nye HLD, Cameron, J., Chernoff EAG and Stocum DL (2003) Extending theTable of Stages of Normal Development of the Axolotl: Limb Development. Devel Dyn 226:555-560 (Cover picture).
• Showalter AD, Yaden BC, Chernoff EAG and Rhodes SJ (2003) Cloning and Analysis of Axolotl ISL2 and LHX2 LIM-Homeodomain Transcription Factors. Genesis (Developmental Genetics) 38:110-121.
• Johnson CD, Narasimha Chary S, Chernoff EA, Zeng Q, Running MP, Crowell DN. (2005) Protein Geranylgeranyltransferase I Is Involved in Specific Aspects of Abscisic Acid and Auxin Signaling in Arabidopsis. Plant Physiol. 139:722-733.

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Linda DiMeglio, MD, MPH

Position

• Associate Professor, Pediatrics

Address
Section of Pediatric Endocrinology and Diabetology
Department of Pediatrics
RI 5960
Indiana University School of Medicine
Indiana University-Purdue University Indianapolis
Indianapolis, IN 46202

Phone: (317) 274-3889
Fax: (317) 274-3882
E-mail: dimeglio@iupui.edu

Research Interests

1. Bisphosphonate Therapy for Osteogenesis Imperfecta.

2. Long-Term Insulin Pump Therapy in Very Young Children with Type 1 Diabetes.

3. Diabetes’ Impact on Endothelial Progenitor Cell Function and Vascular Reactivity.

Recent Publications

• DiMeglio LA, Ford L, McClintock C, Peacock M. Intravenous Pamidronate Treatment of Infants with Osteogenesis Imperfecta. Bone. 2004. 35(5):1038-45.
• DiMeglio LA, Ford L, McClintock C, Peacock M. A comparison of oral and intravenous bisphosphonate therapy for children with osteogenesis imperfecta. Journal of Pediatric Endocrinology and Metabolism. 2005. 18(1):43-53.
• Hanna KM, DiMeglio LA, Fortenberry JD. Parent and Adolescent Versions of the Diabetes-specific Parental Support for Adolescents’ Autonomy Scale. Journal of Pediatric Psychology. 2005. 30(3):257-271.
• DiMeglio LA and Peacock M. Two-Year Clinical Trial of Oral Alendronate versus Intravenous Pamidronate in Children with Osteogenesis Imperfecta. Journal of Bone and Mineral Research. 2006. 21(1):132-140.
• Nabhan Z, Eugster EA, Rardin L, Meier J, and DiMeglio LA. Predictors of Glycemic Control on Insulin Pump Therapy in Children and Adolescents with Type I Diabetes. Diabetes Research and Clinical Practice. 2006. 74(3):217-221.

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James A. Marrs, PhD

Positions

• Associate Professor of Medicine
• Associate Professor of Cellular & Integrative Physiology

Address
Department of Medicine, School of Medicine
Indiana University-Purdue University Indianapolis
950 W. Walnut St., R2-223
Indianapolis, IN 46202

Phone: (317) 278-0472
Fax: (317) 274-8575
E-mail: jmarrs@iupui.edu

Research Interests

My research laboratory studies the roles of cell-cell junctional complexes (adherens junctions and tight junctions) in the establishment and maintenance of epithelial cell polarity and the role of cadherin cell adhesion molecules during embryogenesis. Cadherins are a large superfamily of molecules which mediate calcium dependent cell-to-cell adhesion, and these molecules regulate cell adhesiveness, cell survival, cell polarity and cellular differentiation during normal development and during disease processes.

We are also investigating defects in developmental mechanisms produced by ethanol exposure during embryogenesis. Our experiments and those from other laboratories show that zebrafish can be used to model fetal alcohol syndrome (FAS). As ongoing and new animal model research promotes better understanding of the consequences of fetal ethanol exposure in human patients, a key goal is to gain new mechanistic insight into the genesis of FASD. Information gained from novel approaches in animal models will facilitate translational research, with a long-term goal of developing rational approaches to treatment and prevention of this devastating disorder.

Recent Publications

• Liu Q, Londraville RL, Azodi E, Babb SG, Chiappini-Williamson C, Marrs JA, Raymond PA (2002) Up-regulation of cadherin-2 and cadherin-4 in regenerating visual structures of adult zebrafish. Exp Neurol 177: 396-406.
• Babb, SG and Marrs JA (2004) E-cadherin regulates cell movements and tissue formation in early zebrafish embryos. Developmental Dynamics 230: 263-277.
• Babb SG, Kotradi SM, Shah B, Chiappini-Williamson C, Bell LN, Schmeiser G, Chen E, Liu Q and Marrs JA (2005) Zebrafish R-cadherin (Cdh4) controls visual system development and differentiation. Developmental Dynamics 233: 930-945.
• Gopalakrishnan S, Hallett MA, Atkinson S, Marrs JA (2006) aPKC-Par complex dysfunction and tight junction disassembly in renal epithelial cells during ATP-depletion. Am J Physiol Cell Physiol 292: C1094-102.
• Babb-Clendenon S. G., Y.-c. Shen, Q. Liu, K. E. Turner, M. S. Mills, G. W. Cook, C. A. Miller, V. H. Gattone II, K. F. Barald, and J. A. Marrs. 2006. Cadherin-2 participates in the morphogenenesis of the zebrafish inner ear. J. Cell Sci. 119: 5169-5177.
• Liu Q, Frey RA, Babb-Clendenon SG, Liu B, Francl J, Wilson AL, Marrs JA, and Stenkamp DL (2007) Differential expression of photoreceptor-specific genes in the retina of a zebrafish cadherin2 mutant glass onion and zebrafish cadherin4 morphants. Exp Eye Res. 84: 163-175.
• Wilson AL, Shen Y, Babb-Clendenon SG, Rostedt J, Liu B, Barald KF, Marrs JA, and Liu Q (2007) Cadherin4 plays a role in the development of zebrafish cranial ganglia and lateral line system. Developmental Dynamics 236: 893-902.

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Mark Pescovitz, MD

Positions

• Vice Chair for research and Professor Dept of Surgery
• Professor Dept of Microbiology and Immunology

Address
Department of Surgery
University Hospital 4601
Indiana University Medical Center
Indiana University-Purdue University Indianapolis
Indianapolis, IN 46202

Phone: (317) 274-4370
Fax: (317) 278-3268
Email: mpescov@iupui.edu

Research Interests

My research interests are immunosuppression, type 1 diabetes, role of B cells and antibody in rejection of allografts.

Recent Publications

• Wheat, L. J., Connolly, P., Durkin, M., Book, B. K., and Pescovitz, M.D. Elimination of false-positive Histoplasma antigenemia caused by human anti-rabbit antibodies in the second generation Histoplasma antigen assay. Transpl Infect Dis 8:219-221, 2006.
• Jordan, S.C. and Pescovitz, M. D. Presensitization: The problem and its management. Clin J Am Soc Nephrol. 1:421-432, 2006.
• Pescovitz, M.D. Prevention of CMV disease following solid organ transplantation. Future Dir Surg In press, 4/06.
• Jonathan A. Fridell, J. A., Agarwal, A., Powelson, J.A., Goggins, W. C., Milgrom, M., Pescovitz, M. D., Tector, A. J. Steroid withdrawal for pancreas after kidney transplantation in recipients on maintenance prednisone immunosuppression. Transplantation 82:389-392, 2006.
• Pescovitz, M.D. Valganciclovir. Tranpslantation Reviews 20:82-87, 2006.
• Book, B.K., Pescovitz, M.D., Agarwal, A., Hardwick, L.M., Henson, S.L., Milgrom, M.L, Tector, A.J., Sidner, R.A., Volz, M.A, and Filo, R.S. In vitro monitoring of in vivo development of human anti-thymoglobulin antibodies by ELISA. Transplant Proc 38:2869-2871, 2006.

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Simon J. Rhodes, PhD

Positions

• Professor, Department of Cellular and Integrative Physiology
• Professor, Department of Biochemistry and Molecular Biology
• Associate Dean for Graduate Studies, Indiana University School of Medicine
• Adjunct Professor, Department of Biology

Address
Medical Science Building Room 207
Indiana University School of Medicine
Indiana University-Purdue University Indianapolis
635 N. Barnhill Drive
Indianapolis, IN 46202-5120

Phone: (317) 274-3441
Fax: (317) 278-5211
Email: srhodes@iupui.edu

Research Interests

Our laboratory investigates how key regulatory genes direct the determination and differentiation of individual endocrine cell lineages of the brain and pituitary during vertebrate development. For example, the anterior pituitary gland presents a valuable model system to pursue these studies. The mature gland contains five discrete cell types that are each characterized by the secretion of specific polypeptide hormones critical for growth, sexual function, lactation, thyroid activity, adrenal physiology and homeostasis. We use both molecular/ in vitro and transgenic animal approaches to examine the roles of several classes of transcription factors in specification of pituitary cell phenotypes. Our research goals include:

1. Characterization of the basic biology/biochemistry of endocrine transcription factors.
2. Investigation of the molecular nature of human pituitary diseases, such as pituitary tumors and growth disorders in children, in collaboration with faculty at Riley Children's Hospital.
3. The analysis of the gene regulatory pathways that control growth, metabolism, and reproductive fitness in agricultural species, in collaboration with the U.S. Meat Animal Research Center.

Other projects in the lab include investigation of bone transcription factors in collaboration with Dr. Joseph Bidwell of the Indiana University School of Medicine at IUPUI, and molecular studies of nervous system regeneration in amphibians in collaboration with Dr. Ellen Chernoff of the IUPUI Biology Department.

Recent Publications

• Savage, J.J., Mullen, R.D., Sloop, Colvin, S.C., Camper, S.A., Franklin, C.L. and Rhodes, S.J. (2007). Transgenic Mice Expressing LHX3 Transcription Factor Isoforms in the Pituitary: Effects on the Gonadotrope Axis and Sex-Specific Reproductive Disease. J. Cell. Physiol, In Press.
• Mullen, R.D., Colvin, S.C., Hunter, C.H., Savage, J.J., Walvoord, E.C., Bhangoo, A.P.S., Ten, T., Weigel, J., Pfäffle, R.W., and Rhodes, S.J. (2007). Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development. Mol. Cell. Endocrinol. in press.
• Durán-Prado, M., Bucharles, C., Gonzalez, B.J., Vázquez-Martínez, R., Martínez-Fuentes, A.J., García-Navarro, S., Rhodes, S.J. Vaudry, H., Malagón, M.M., and Castaño, J.P. 2006. Porcine somatostatin receptor 2 displays typical pharmacological sst2 features but unique dynamics of homodimerization and internalization. Endocrinology, in press.
• Granger, A., Bleux, C., Kottler, M.-L., Rhodes, S.J., Counis, R., and Laverrière, J.-N. (2006). The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor-1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter. Mol. Endocrinol. 20: 2093-2108. Epub 2006 Apr 13.
• Bhangoo, A.P.S., Hunter, C.S., Savage, J.J., Anhalt H, Pavlakis S, Walvoord E.C., Ten, S., and Rhodes, S.J. (2006). A novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J. Clin. Endocrinol. Metab. 91: 747-753. Epub 2006 Jan 4.

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Randall J. Roper, PhD

Position

• Assistant Professor

Address
Department of Biology
School of Science
Indiana University-Purdue University Indianapolis
723 W. Michigan St., SL306
Indianapolis, IN 46202

Phone: (317) 274-8131
Fax: (317) 274-2846
E-mail: rjroper@iupui.edu

Research Interests

The neural crest is a transient population of cells found during early embryogenesis and has been termed the “fourth germ layer” because of its developmental mulitpotency. Several tissues with a neural crest component, including craniofacial skeleton, peripheral nervous system, heart, and digestive tract, are affected in individuals with Down syndrome. It has therefore been hypothesized that trisomy 21 causes defects in neural crest cells (NCC). Our work with mouse models of Down syndrome provided the first experimental evidence that trisomy affects neural crest precursors of craniofacial skeleton. Our laboratory is interested in understanding how dosage imbalance of genes on human chromosome 21 affects NCC during development and leads to phenotypes associated with Down syndrome. The deficits caused by trisomy may involve the generation, migration, proliferation, or differentiation of NCC. Using mouse models and in vitro culture systems we want to understand the cellular, genetic, and molecular mechanisms leading to trisomic NCC deficiencies, and identify temporally and spatially specific points for intervention. The long range goal of our work is to discover a molecular therapy to prevent or correct neural crest-related abnormalities in individuals with trisomy.

Recent Publications

• Roper, RJ, Reeves, RH. Understanding the basis for Down syndrome phenotypes. PLoS Genet. 2006 Mar;2(3):e50.
• Roper, RJ, Baxter, LL, Saran, NG, Klinedinst, DK, Beachy, PA, Reeves, RH. Defective cerebellar response to mitogenic Hedgehog signaling in Down syndrome mice.
• Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1452-6. Epub 2006 Jan 23.
• Roper, RJ, St John, HK, Philip, J, Lawler, A, Reeves, RH. Perinatal loss of Ts65Dn Down syndrome mice. Genetics. 2006 Jan;172(1):437-43. Epub 2005 Sep 19.
• Olson LE, Roper RJ, Baxter LL, Carlson EJ, Epstein CJ, Reeves RH. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev Dyn. 2004 Jul;230(3):581-9.

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John H. Schild, PhD

Positions

• Associate Professor, Biomedical Engineering Department
• Adjunct Assistant Professor, Department of Biology

Address
Department of Biomedical Engineering
SL 174
School of Engineering and Technology
723 W. Michigan St
Indianapolis, IN 46202

Phone: (317) 274-9747
Fax: (317) 278-2032
Email: jschild@iupui.edu

Research Interests

More than 64 million Americans have some form of cardiovascular disease, the most prevalent being high blood pressure, myocardial infarction and angina pectoris also known as cardiac pain (The American Heart Association, 2004). While the clinical manifestations of these diseases are well described, comparatively little is known regarding the neural mechanisms underlying the control of the heart and circulation. We utilize a combination of experimental and computational techniques in developing a functional understanding of how individual cardiac sensory neurons and brainstem neural circuits both encode and process cardiovascular information. Fundamental to the operation of all neurons are ion channels, which are membrane bound proteins that give rise to the electrical characteristics of these cells. Ion channels or subcellular modulators of ion channel function are often targets for pharmacological interventions in treating cardiovascular disease. In the laboratory, we use patch clamp electrophysiology to study the impact of ion channel dynamics upon the discharge characteristics of cardiac sensory neurons. In the computer, we use biologically realistic mathematical models of cardiac sensory neurons and techniques of dynamical systems analysis to provide a conceptual framework with which to meaningfully interpret experimental results as well as a way of better directing and organizing future studies. An additional aspect of our work involves the development of instrumentation that moves our theoretical models out of the computer and into the research laboratory where they can be used as real-time tools for studying ion channel dynamics. Know as Dynamic Current Clamping, this technique makes possible the biological testing of model-based hypothesis as well as the study of higher order models of ion channel structure and function, which previously could not be validated experimentally. Recent results from our lab have demonstrated how tetrodotoxin-resistant Na+ ion channels, a special class of ion channels closely associated with pain sensation, can exert considerable influence over the responsiveness of a particular class of cardiac sensory neurons. We anticipate that these results may lead to more efficient development and effective application of pharmacological interventions for the management of cardiac pain.

Recent Publications

• Jin YH, Bailey TW, Li BY, Schild JH, Andresen MC. P2X and VR1 receptor activation releases glutamate from separate cranial afferent terminals in nucleus tractus solitarius. Journal of Neuroscience, Vol. 24(20), 4709-4717, 2004.
• Jin YH, Bailey TW, Doyle MW, Li BY, Chang SK, Schild JH, Mendelowitz D, and Andresen MC. Ketamine differentially blocks sensory afferent synaptic transmission in medial nucleus tractus solitarius (mNTS). Anesthesiology. Vol. 98(1), 121-32, 2003.
• Li BY and Schild JH. Patch clamp electrophysiology in the nodose ganglia of the adult rat. J. Neuroscience Methods, Vol. 115(2), 157-67, 2002.
• Glazebrook PA, Ramirez AN, Schild JH, Shieh CC, Doan T, Wible BA, Kunze DL. Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons. J. of Physiology, Vol. 541, 467-82, 2002.
• Schild JH, Kunze DL. An experimental and modeling study of Na+ current heterogeneity in rat nodose neurons and its impact on neuronal discharge. J. Neurophysiology, Vol. 78, 3198-3209, 1997.

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Feng C. Zhou, PhD

Position

• Professor of Anatomy, Cell Biology and Neurobiology, Stark Neuroscience Research Institute

Address
Department of Anatomy and Cell Biology
MS 508
Indiana University School of Medicine
Indiana University-Purdue University Indianapolis
635 Barnhill Drive
Indianapolis, IN 46202

Phone: (317) 274-7359
Fax: (317) 274-3912
E-mail: imce100@iupui.edu

Research Interests

The research theme in my laboratory is Neuroadaptation which includes: Neurobiology of substance abuse and neurodevelopmental and neurodegenerative disorders. The neural system as a whole has an intricate (re)molding ability: environmental impact has the potential to alter gene expression or epigenetic modification, to reprogram neurodevelopmental sequence and pathway, and to modify adult functional pathways and synaptic & receptor plasticity. These (re)molding abilities are collectively called Neuroadaptation. It is neuroadaptation that may underlie the mechanisms of substance abuse, altered state of mind, and neurodegenerative / neurodevelopmental disorders.

Fetal Alcohol Syndrome: Women drinking during pregnancy give birth to children with growth retardation, neural development deficit, and facial dysmorphology know as fetal alcohol syndrome (FAS). We are interested in studying deficits resulting from FAS, including serotonin and sensory cortical systems, mechanism via epigenetic and developmental gene (bHLH, neurogenin and NKX2.2) alteration, and treatment using neurotrophic peptides.

Alcohol Abuse and Synaptic Adaptation: Repeated high alcohol intake induces neuroadaptation. We investigate how chronic alcohol exposure alters the brain into an “addictive” state using two-photon microscopy to monitor presynaptic glutamate and dopamine terminals and postsynaptic NMDA, AMPA, mGluR receptors on dendritic spines in the reward circuitry.

Neural Stem Cells and Neurodegenerative Disease: We are interested in injury spinal cord injury and Parkinsonism and their treatment using embryonic stem (ES) and adult neural stem cells, and molecular genetic approaches.

Recent Publications

• Zhou, F.C. and R. P. Singh (2003) Regulation of neural stem cells in the adult mammalian brain, In Neuronal and Vascular Plasticity: Elucidating Basic Cellular Mechanisms for Future Therapeutic Discovery. Chap 9. P219-256. Kluwer Academic Publishers. New York
• Powrozek, TA, Sari, Y. Singh, RP, and F.C. Zhou. Neurotransmitters and drugs of abuse: effects on adult neurogenesis, Current Neurovascular Res. 1 (2004)252-260
• Ogawa T, Kuwagata M, Ruiz J, and Zhou F.C. (2005) Differential teratogenic effect of alcohol on embryonic development between C57BL/6 and DBA/2 Mice: A new view. Alcohol Clin Exp Res., 29:855-63.
• Zhou F.C., Sari, Y, Powrozek T, and Spong CY. A neuroprotective peptide antagonizes fetal alcohol exposure compromised brain growth. J. Mole. Neurosci, 24(2004)189-199.
• Chiang YH, Lin SZ, Zhou F.C. Bridging nigrostriatal pathway with fibroblast growth factor-primed peripheral nerves and fetal ventral mesencephalon transplant recuperates from deficits in parkinsonian rats. Cell Transplant. 2006;15(6):475-82

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