Preclinical and Translational Research Projects

Neurotrauma, Neuroproteomics & Biomarkers Research (NNBR)


Current Team

Kevin K Wang

Kevin K Wang Ph.D.

Professor & Program Director NNBR
Firas H Kobaissy

Firas H Kobaissy Ph.D.

Research Assistant Professor & Associate Director NNBR
Zhihui Yang

Zhihui Yang Ph.D.

RES AST PROF
Haiyan Xu

Haiyan Xu

Biological Scientist II
Fan Lin

Fan Lin

Research Assistant II
Kefren Arjona

Kefren Arjona

Biological Scientist I
Jiepei Zhu

Jiepei Zhu MD, PhD

Assistant Professor Of Anesthesiology & Affiliated Researcher NNBR

Current Studies

 Analytical Validation of Tau and P-Tau as Acute and Subacute Diagnostic Biomarkers for Complicated mild TBI

  •  Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Firas Kobeissy PhD, Haiyan Xu, Fan Lin
  • Grant/ Contract Number (PI):  1 U01 NS111680-01
  • Supporting Agency: NIH-NINDS
  • Performance Period:  4/1/2020 – 3/31/2025

Brief Description of Project Goals:  Emerging literature evidence and our own data point to blood-based Tau/P-Tau levels can fill these unmet biomarker needs. We propose two types of context of use (COU) for Tau/ P-Tau as prognostic biomarkers for complicated mild TBI patients at risk for persistent post-concussive symptoms lasting more than 3 months.

Aims: (1) create Tau and P-Tau gold standards and pooled positive/negative controls samples for use in Tau/P-Tau platform testing and standardization, (2) assess the analytical performance of new assay platforms for Tau/P-Tau at two analytical sites, (3) establish the baseline blood levels of Tau and P-Tau in normative controls of different adult age intervals, (4) provide supportive data for acute/subacute Tau and P-Tau levels as blood-based biomarker for the indicated COU,  (5) establish the temporal profile of blood Tau, P-Tau levels in TBI patients of varying severity and injury types, and lastly (6) assemble Tau/P-Tau TBI biomarker qualification plan for submission to FDA’s  Biomarker Qualification Program.


NIBA-TBI: Neuro-Imaging and biofluid-based Biomarker Assessments as translational pathophysiological outcome measures in TBI

  • Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Febo Marcelo, Jiepei Zhu MD PhD, Kefren Arjona, Daniel Arja MD
  • Grant/ Contract Number (PI): 1 UG3 NS106938-01 / UH3 NS106938-01
  • Supporting Agency: NIH-NINDS
  • Performance Period: 5/1/2018 – 4/30/2023

Aims: To develop and verify utilities of translatable tools in multiple animal TBI models in assessing pathomechanistic subtypes of TBI, including MR-neuroimaging and biofluid-based protein biomarkers.


TRACK-TBI Precision Medicine – Pathomechanistic Classification of Traumatic Brain Injury: The Bridge to Targeted Therapies

  • Principal Investigator: Geoff Manley, UCSF
  • Co-Investigators: Kevin Wang PhD, Zhihui Yang, PhD, Haiyan Xu, Fan Lin
  • Grant/ Contract Number (PI): Precision Trauma.  # W81XWH-18-2-0042 (DM180187)
  • Supporting Agency: DOD/ DMRDP
  • Performance Period: 5/1/2018 – 4/30/2023

Brief Description of Project Goals:  We hypothesize that generating biofluid-based biomarker panels will identify the major TBI subphenotypes in the acute, subacute and chronic phases. Our objectives are to: establish an Exploratory phase (year 1) to obtain biofluid biomarker data on TBI subphenotypes from sTBI patients at the acute, subacute and chronic stages. We will utilize the Exploratory phase data to verify our results on new moderate/severe patient TBI subphenotype samples obtained at the acute/subacute phase (Verification Phase – year 2) and at the chronic stage (Verification Phase – year 3)

AIMS: (1) – Exploratory Phase/ BASE (year 1)  Analyze a panel of selected biomarkers on archived human CSF/blood samples obtained at acute, subacute, and chronic phases from patients with identified TBI subphenotypes.  (2) – Verification Phase / Option I (year 2): Using the data generated in  Exploratory Phase to “down-selected” TBI biomarker subpanel to distinguish key acute TBI subphenotypes (DAI, contusion, hematoma, fiber track/white matter degeneration, hypopituitarism) with new biosamples from two cohorts (BC and UPMC)   (3) – Verification Phase / Option II period (year 3). Utilize additional new patient biofluid samples to verify our “down-selected” TBI biomarker subpanel can distinguish key “chronic TBI subphenotypes” using biosamples from two cohorts: chronic sTBI subjects at UPMC neurorehabilitation center, and the MRVA-BRRC


Biomarker-Based Precision Medicine Approach to Traumatic Brain Injury Subphenotypes

  • Principal Investigator: R. Rubenstein, SUNY
  • Site Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Haiyan Xu, Fan Lin
  • Grant/ Contract Number (PI): DM180041
  • Supporting Agency: DOD – DMRDP
  • Performance Period: 5/1/2019 – 4/30/2022

Brief Description of Project Goals:  We hypothesize that generating biofluid-based biomarker panels will identify the major TBI subphenotypes in the acute, subacute and chronic phases. Our objectives are to: establish an Exploratory phase (year 1) to obtain biofluid biomarker data on TBI subphenotypes from sTBI patients at the acute, subacute and chronic stages. We will utilize the Exploratory phase data to verify our results on new moderate/severe patient TBI subphenotype samples obtained at the acute/subacute phase (Verification Phase – year 2) and at the chronic stage (Verification Phase – year 3)

AIMS: (1) – Exploratory Phase/ BASE (year 1)  Analyze a panel of selected biomarkers on archived human CSF/blood samples obtained at acute, subacute, and chronic phases from patients with identified TBI subphenotypes.  (2) – Verification Phase / Option I (year 2): Using the data generated in  Exploratory Phase to “down-selected” TBI biomarker subpanel to distinguish key acute TBI subphenotypes (DAI, contusion, hematoma, fiber track/white matter degeneration, hypopituitarism) with new biosamples from two cohorts (BC and UPMC)   (3) – Verification Phase / Option II period (year 3). Utilize additional new patient biofluid samples to verify our “down-selected” TBI biomarker subpanel can distinguish key “chronic TBI subphenotypes” using biosamples from two cohorts: chronic sTBI subjects at UPMC neurorehabilitation center, and the MRVA-BRRC


Identifying proteomic, metabolomic and microRNA biomarkers signifying spontaneous post-traumatic epilepsy in a rat model of penetrating ballistic brain injury

  • Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Logan Patterson, Haiyan Xu
  • Grant/ Contract Number (PI): 4837842018 – 2022
  • Supporting Agency: CURE Foundation TBI-post-traumatic Epilepsy
  • Performance Period: 9/1/2018 – 4/30/2021

Brief Description of Project Goals:  To conduct parallel proteomic, metabolomic and microRNA biomarker analysis and define biosignature signifying spontaneous post-traumatic epilepsy in a rat model of penetrating brain injury

Aims:  Using rat model of penetrating brain injury to examine the development of post-traumatic epilepsy and proteomic, miRNA and metabolomic biomarker signatures. 9/1/2018 – 4/30/2021

To identify biosignatures that link to the formation of post-TBI nonconvulsive seizure in a rat model of penetrating ballistic-like brain injury


Combinatorial Biosignatures of Network Dysfunction to Predict Post-Traumatic Epilepsy: Clinical Translation from a Robust Mouse Model

  • Principal Investigator: E. Zanier, MARIO NEGRI INSTITUTE
  • Site Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Logan Patterson, Haiyan Xu
  • Grant/ Contract Number (PI): EP180028
  • Supporting Agency: DOD-CDMRP
  • Performance Period: 2019 – 2022

Brief Description of Project Goals: The project examine using a CD-1 mouse model of controlled cortical impact-induced TBI the combinatorial biosignatures of network dysfunction to predict post-traumatic epilepsy (PTE). These methods include proteomics biomarkers, miRNA biomarkers and autoantibody biomarkers. In addition, we will also verify these biomarker candidates in human TBI patients with and without PTE.

Aims:  Aim 1 – To monitor PTE development by ECoG and brain MRI analyses; Aim 2 –  To monitor PTE development by combinatorial biosignatures; and Specific Aim 3: To perform a preliminary clinical verification study in TBI patients with/without PTE


TRACK-TBI NET: Transforming Research and Clinical Knowledge in Traumatic Brain Injury Network

  • Principal Investigator: G. Manley- UCSF
  • Site Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Logan Patterson, Haiyan Xu
  • Grant/ Contract Number (PI): MTEC-18-03-DTTBI-0001 / 11153sc
  • Supporting Agency: DOD / MTEC
  • Performance Period: 10/1/2018– 9/30/2023

Brief Description of Project Goals: Acute TBI patients are still divided into crude categories of mild, moderate, and severe, using the Glasgow Coma Scale (GCS) and basic radiological stratification of CT findings as positive or negative. For nearly 10 years, TRACK-TBI investigators have taken a precision medicine approach to identify and validate new diagnostic and prognostic neuroimaging and blood-based biomarkers of TBI.

AimsComponent 1: TRACK-TBI NET will enroll subjects from civilian Level 1 Trauma Centers, yet the predominant mechanisms of injury of diffuse axonal and vascular injuries, contusions, mass lesions, and secondary brain insult are the same as seen in blast and non-blast related, moderate to severe, military TBI. Component 2 we are prepared to conduct the first clinical trials in which cohorts will be enriched and subjects stratified according to neuroimaging and molecular measures of injury.   Component 3. Candidate medications designed to reduce secondary brain insult will be initiated in the acute post-injury period (likely within 24h), anticipating their use in forward hospitals or clinics or in regional trauma centers.


Malcolm Randell VAMC    (VA joint appointment – K. Wang)

Merit Award: Chronic neurodegenerative and behavioral changes associated with repetitive closed head injury in mice

  • Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Firas Kobeissy PhD, Fan Lin
  • Grant/ Contract Number (PI): VA Merit Award Project ID: B1859-I (eRA #: I01 RX001859 A02)
  • Name and Address of Agency’s Contracts/Grants Officer:  Stuart Hoffman (Stuart.Hoffman@va.gov)
  • Supporting Agency: Veterans Administration (VA)
  • Performance Period: 12/01/2016 – 11/30/2020

Brief Description of Project Goals: The primary goal of this proposal is to examine our Central Hypothesis that chronic cognitive and neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43 proteinopathy development.

Specific Aims:   Specific Aim 1, Subject wildtype mice to single and repetitive close head injury (rCHI) and follow them from subacute to chronic period to characterize cognitive and neurobehavioral changes and its correlation with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation signatures in brain tissue and biofluid. Specific Aim 2. Subject hTau transgenic mice and TDP-43 overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they develop worsened cognitive and neurobehavioral changes, and accelerated, exaggerated Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid.   Specific Aim 3, Test potential effects of anti-Tau and/or anti-TDP-43 monoclonal antibodies as immunotherapy on reducing combined Tau and TDP-43-proteinopathy load and chronic neurobehavioral changes.


Mild Traumatic Brain Injury and Opiate Exposure Cross-talk: Neuropathological, Neurobehavioral, and Neuroproteomic Assessments

  • Principal Investigator: Kevin Wang PhD
  • Co-Investigators: Zhihui Yang, PhD, Firas Kobeissy PhD, Jiepei Zhu MD PhD, Fan Lin
  • Grant/ Contract Number (PI): VA SPIRE Award Project ID: 12151 (eRA #:  1 I21 RX003192-01
  • Name and Address of Agency’s Contracts/Grants Officer:  Stuart Hoffman (Stuart.Hoffman@va.gov)
  • Supporting Agency: Veterans Administration (VA)
  • Performance Period: 11/01/2019 – 10/31/2021

Brief Description of Project Goals: To examine if mild TBI with opiate exposure will contribute to worsened Neuropathological, Neurobehavioral outcome in a mouse model.

Aims:   Specific Aim 1: Determine the effects of 1-month fentanyl opiate exposure post-rCHI followed by 1 month withdrawal on: cognition, pain sensation, motor activity and spontaneous opiate withdrawal symptoms. Specific Aim 2: Assess key cellular -neuropathological markers and opiate receptor levels in three brain regions (cortex, hippocampus and ventral tegmental area) implicated in TBI and/or opioid receptor-mediated reward circuits. Specific Aim 3: Identify and analyze “Pathways/Key Drivers” related to long-term mTBI consequences and opiate abuse comorbidity as putative neurotherapeutic targets using an advanced differential neuroproteomic and System Biology platforms.