Faculty

Back to Index
Zhen Zhao, PhD
Assistant Professor of Physiology & Biophysics
Zilkha Neurogenetic Institute
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

Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci. 2017 Jan 30. View in: PubMed

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

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

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

Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015 Nov 19; 163(5):1064-78. View in: PubMed

Central role for PICALM in amyloid-ß blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015 Jul; 18(7):978-87. View in: PubMed

Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21; 85(2):296-302. View in: PubMed

Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nat Commun. 2015; 6:7839. View in: PubMed

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

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

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

Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun. 2014; 5:4820. View in: PubMed

Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013 Dec 13; 4:2932. View in: PubMed

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

CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization. Dev Neurobiol. 2013 Sep; 73(9):673-87. View in: PubMed

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

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

UVRAG: At the crossroad of autophagy and genomic stability. Autophagy. 2012 Sep 1; 8(9):1392-3. View in: PubMed

A Dual Role for UVRAG in Maintaining Chromosomal Stability Independent of Autophagy. Dev Cell. 2012 May 15; 22(5):1001-16. View in: PubMed

Anti-autophagic Bcl-2: Not just an innocent bystander. Autophagy. 2011 Feb; 7(2):231-2. View in: PubMed

Measurement of γHV68 Infection in Mice. J Vis Exp. 2011; (57). View in: PubMed

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

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

The transduction channel TRPM5 is gated by intracellular calcium in taste cells. J Neurosci. 2007 May 23; 27(21):5777-86. View in: PubMed

Powered bySC CTSI