Zhen Zhao, 2017-04-29T04:46:36+00:00
 

Faculty

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Zhen Zhao, PhD
Assistant Professor of Physiology & Biophysics
Physiology and Biophysics
ZNI 301 1501 San Pablo Street Health Sciences Campus Los Angeles
+1 323 442 2484

Overview

Research Directions

i) To search for the genetic causes of vascular cognitive impairment and dementia
50 million people worldwide are now suffering from dementia; however, the exact causes remain elusive. Vascular Cognitive Impairment and Dementia (VCID) due to cerebrovascular diseases and pathologies represents 20~40% of the dementia cases, and largely overlaps with AD in terms of pathologies and pathogenic factors. Recently, we have been working with two groups of genetic risk factors that are vascular residents but can either predispose individual to cerebrovascular diseases or strongly modify the course of AD and VCID, such as platelet-derived growth factor receptor beta (PDGFRß), LRP1 and PICALM. Although this is just the first peek through the looking glass, yet our finding has brought new insight into the genetic causes of VCID and AD, suggesting that a better understanding the etiology and pathogenesis of AD and VICD, especially decoding the common genetic causes may help us redefining a subset of cases, and land more effective therapeutics for them in the near future.

ii) To study the molecular mechanism of the receptor-mediated transport at the blood-brain barrier
Receptor-mediated transcytosis (RMT) provides a major clearance pathway for Aß at the BBB, by flushing Aß out from brain to circulation. However, the understanding of this unique system remains limited, particularly regarding the molecular machinery which drives the cargos through multiple transcytosis events, including receptor-mediated endocytosis, intracellular trafficking, and exocytosis, as well as avoids the degradation pathway through late endosomes and lysosomes. Impaired vascular Aß clearance leads to elevated brain Aß level and exacerbates AD pathology. Piling evidence indicates that the alteration in the RMT system, particularly abnormal expression of AD vascular risk genes in the cerebral vasculature, contributes to pathogenesis. By studying the PICALM-dependent transvascular RMT machinery, we also hope to identify new key molecular targets of the BBB, which can be or manipulated pharmacologically or by adeno-associated virus (AAV)-mediated gene delivery, for more effective CNS drug delivery across the BBB.

iii) To examine the crosstalk between the cells within the neurovascular unit
Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit (NVU). The cells of the NVU are not just adjacently located and structurally connected; they communicated with each other vigorously via different signaling modules in order to function in orchestration. Such crosstalk is achieved by various cellular mechanisms, including but not limited to signaling receptors and channels, microRNA-containing exosomal vehicles (EVs) and gap junction-mediated direct exchange of small molecules. Neurovascular congruency is essential for the proper patterning of the CNS during development and neurovascular interaction is critical for normal brain functions, while its dysfunctions contribute to the pathogenesis of CNS injuries and neurodegenerative diseases, such as stroke and Alzheimer’s disease. We expect to provide evidence of functional pericyte–neuron crosstalk for brain health and functions, as well as pericyte contribution to brain’s innate immunity during CNS diseases or viral infections.

Publications

Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžic S, Zlokovic BV. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci. 2017 Jan 30. View in: PubMed

Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžic S, Zlokovic BV. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci. 2017 Jan 30. View in: PubMed

Wang Y, Zhao Z, Rege SV, Wang M, Si G, Zhou Y, Wang S, Griffin JH, Goldman SA, Zlokovic BV. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nat Med. 2016 Sep; 22(9):1050-5. View in: PubMed

Liang Q, Luo Z, Zeng J, Chen W, Foo SS, Lee SA, Ge J, Wang S, Goldman SA, Zlokovic BV, Zhao Z, Jung JU. Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell. 2016 Aug 9. View in: PubMed

Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2016 Jan; 36(1):216-27. View in: PubMed

Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015 Nov 19; 163(5):1064-78. View in: PubMed

Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, Winkler EA, Ramanathan A, Kanekiyo T, Bu G, Owens NC, Rege SV, Si G, Ahuja A, Zhu D, Miller CA, Schneider JA, Maeda M, Maeda T, Sugawara T, Ichida JK, Zlokovic BV. Central role for PICALM in amyloid-ß blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015 Jul; 18(7):978-87. View in: PubMed

Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S, Kong P, Nelson AR, Sullivan JS, Zhao Z, Meiselman HJ, Wenby RB, Soto J, Abel ED, Makshanoff J, Zuniga E, De Vivo DC, Zlokovic BV. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci. 2015 Apr; 18(4):521-30. View in: PubMed

Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21; 85(2):296-302. View in: PubMed

He S, Zhao Z, Yang Y, O'Connell D, Zhang X, Oh S, Ma B, Lee JH, Zhang T, Varghese B, Yip J, Dolatshahi Pirooz S, Li M, Zhang Y, Li GM, Ellen Martin S, Machida K, Liang C. Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nat Commun. 2015; 6:7839. View in: PubMed

Zhao Z, Zlokovic BV. Blood-Brain Barrier: A Dual Life of MFSD2A? Neuron. 2014 May 21; 82(4):728-30. View in: PubMed

Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JH, Cleveland DW, Zlokovic BV. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A. 2014 Mar 18; 111(11):E1035-42. View in: PubMed

Pirooz SD, He S, Zhang T, Zhang X, Zhao Z, Oh S, O'Connell D, Khalilzadeh P, Amini-Bavil-Olyaee S, Farzan M, Liang C. UVRAG is required for virus entry through combinatorial interaction with the class C-Vps complex and SNAREs. Proc Natl Acad Sci U S A. 2014 Feb 18; 111(7):2716-21. View in: PubMed

Shi M, Cho H, Inn KS, Yang A, Zhao Z, Liang Q, Versteeg GA, Amini-Bavil-Olyaee S, Wong LY, Zlokovic BV, Park HS, García-Sastre A, Jung JU. Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun. 2014; 5:4820. View in: PubMed

Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013 Dec 13; 4:2932. View in: PubMed

Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, Zlokovic BV. Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats. Stroke. 2013 Dec; 44(12):3529-36. View in: PubMed

He S, Ni D, Ma B, Lee JH, Zhang T, Ghozalli I, Pirooz SD, Zhao Z, Bharatham N, Li B, Oh S, Lee WH, Takahashi Y, Wang HG, Minassian A, Feng P, Deretic V, Pepperkok R, Tagaya M, Yoon HS, Liang C. PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex. Nat Cell Biol. 2013 Oct; 15(10):1206-19. View in: PubMed

Xia C, Nguyen M, Garrison AK, Zhao Z, Wang Z, Sutherland C, Ma L. CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization. Dev Neurobiol. 2013 Sep; 73(9):673-87. View in: PubMed

Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV. Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. Brain Res. 2013 Apr 24; 1507:97-104. View in: PubMed

Guo H, Zhao Z, Yang Q, Wang M, Bell RD, Wang S, Chow N, Davis TP, Griffin JH, Goldman SA, Zlokovic BV. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J Neurosci. 2013 Apr 3; 33(14):6181-90. View in: PubMed

Zhao Z, Ni D, Ghozalli I, Pirooz SD, Ma B, Liang C. UVRAG: At the crossroad of autophagy and genomic stability. Autophagy. 2012 Sep 1; 8(9):1392-3. View in: PubMed

Zhao Z, Oh S, Li D, Ni D, Pirooz SD, Lee JH, Yang S, Lee JY, Ghozalli I, Costanzo V, Stark JM, Liang C. A Dual Role for UVRAG in Maintaining Chromosomal Stability Independent of Autophagy. Dev Cell. 2012 May 15; 22(5):1001-16. View in: PubMed

Oh S, Pirooz SD, Ni D, Zhao Z, Liang C. Anti-autophagic Bcl-2: Not just an innocent bystander. Autophagy. 2011 Feb; 7(2):231-2. View in: PubMed

Pirooz SD, Lee JH, Zhao Z, Ni D, Oh S, Liang C. Measurement of γHV68 Infection in Mice. J Vis Exp. 2011; (57). View in: PubMed

Zhao Z, Ma L. Regulation of axonal development by natriuretic peptide hormones. Proc Natl Acad Sci U S A. 2009 Oct 20; 106(42):18016-21. View in: PubMed

Zhao Z, Wang Z, Gu Y, Feil R, Hofmann F, Ma L. Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons. J Neurosci. 2009 Feb 4; 29(5):1350-60. View in: PubMed

Zhang Z, Zhao Z, Margolskee R, Liman E. The transduction channel TRPM5 is gated by intracellular calcium in taste cells. J Neurosci. 2007 May 23; 27(21):5777-86. View in: PubMed

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